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Mechanistic Insights into the Pharmacological Significance of Silymarin

Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, Haryana, India
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra 136119, Haryana, India
M.M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Ambala 133207, Haryana, India
Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology (MIET), Meerut 250005, Uttar Pradesh, India
Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, Delhi, India
Department of Pharmacy, G.D. Goenka University, Sohna Road, Gurugram 122103, Haryana, India
Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India
Research Unit-Induced Resistance and Plant Bioprotection, University of Reims, EA 4707-USC INRAe 1488, SFR Condorcet FR CNRS 3417, 51687 Reims, France
Authors to whom correspondence should be addressed.
Molecules 2022, 27(16), 5327;
Submission received: 13 July 2022 / Revised: 17 August 2022 / Accepted: 18 August 2022 / Published: 21 August 2022
(This article belongs to the Collection Featured Reviews in Natural Products Chemistry)


Medicinal plants are considered the reservoir of diverse therapeutic agents and have been traditionally employed worldwide to heal various ailments for several decades. Silymarin is a plant-derived mixture of polyphenolic flavonoids originating from the fruits and akenes of Silybum marianum and contains three flavonolignans, silibinins (silybins), silychristin and silydianin, along with taxifolin. Silybins are the major constituents in silymarin with almost 70–80% abundance and are accountable for most of the observed therapeutic activity. Silymarin has also been acknowledged from the ancient period and is utilized in European and Asian systems of traditional medicine for treating various liver disorders. The contemporary literature reveals that silymarin is employed significantly as a neuroprotective, hepatoprotective, cardioprotective, antioxidant, anti-cancer, anti-diabetic, anti-viral, anti-hypertensive, immunomodulator, anti-inflammatory, photoprotective and detoxification agent by targeting various cellular and molecular pathways, including MAPK, mTOR, β-catenin and Akt, different receptors and growth factors, as well as inhibiting numerous enzymes and the gene expression of several apoptotic proteins and inflammatory cytokines. Therefore, the current review aims to recapitulate and update the existing knowledge regarding the pharmacological potential of silymarin as evidenced by vast cellular, animal, and clinical studies, with a particular emphasis on its mechanisms of action.

1. Introduction

Herbal medicaments have been commonly utilized as therapeutic moieties across the globe for therapy and management of a wide array of ailments. Despite the vast advancements in the current medicinal system, medicinal plants still play an imperative role in humans’ well-being [1]. From ancient times, numerous indigenous plants have been employed worldwide to treat various illnesses. Among the diversity of medicinal plants, Silybum marianum, one of the most primordial and systematically researched plants, has been widely employed from ancient times as a natural medication for various liver diseases and some digestive issues of the upper gastrointestinal tract [2]. Indeed, S. marianum, belonging to the Asteraceae/Compositae family, is commonly named ‘milk thistle’ because of the presence of milky white veins on its leaves, which on breakage liberate a milky sap [3]. It is an inhabitant of the Mediterranean but has also grown for centuries all through North Africa, Europe and the Middle East region. In India, this plant is commonly found in Jammu and Kashmir at 1800–2400 m [4]. Silymarin, the standardized seed extract of milk thistle, has been extensively utilized as a broad-spectrum medicinal herb for a very long time [5,6]. From an ethnopharmacological point of view, silymarin has been employed for more than two centuries as a herbal therapy for protecting the liver from varied toxic matters, treating hepatic damage and for treatment of hepatitis as well cirrhosis [7,8]. Silymarin has also been used as an antidote for insect stings, snake bites, mushroom poisoning and alcohol [9,10,11].
Chemically, silymarin is a polyphenolic flavonoid extract consisting of about 70–80% silymarin flavonolignans along with 20–35% fatty acids and several other polyphenolic components [12]. Amongst all flavonolignans, silibinin (silybin), (2R,3R)-3,5,7-trihydroxy-2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydrobenzo [b][1,4]dioxin-6-yl]chroman-4-one (Figure 1), is the foremost active compound present in silymarin with almost 60–70% abundance and exists in the form of two diastereomers, silybin A and silybin B [13]. The pathways for silybin biosynthesis are somehow not clearly identified, but specific biomimetic syntheses assert that the coupling of taxifolin and coniferyl alcohol via peroxidase activity leads to silybin formation [14,15]. The other flavonolignans available in silymarin consist of isosilybin (5%), silychristin (20%) and silydianin (10%). As with silybin, isosilybin also naturally occurs in two diastereomeric forms, i.e., isosilybin A and isosilybin B (Figure 1). Some minor flavonolignans that are also present in silymarin include silimonin and isosilychristin [16]. Apart from flavonolignans, taxifolin is an essential flavonoid found in silymarin [17,18,19].
Evidence from preclinical and clinical research has revealed that silymarin and its flavonolignans significantly impart antioxidant, anti-inflammatory and pro-apoptotic properties, inducing numerous biological and pharmacological activities, for instance, hepatoprotection, neuroprotection, anti-diabetic properties, anti-cancer properties, cardioprotection, photoprotection, immunomodulation and many more. In the United States, there is no quality control and regulation of herbal compounds such as silymarin as they are not considered drugs and are not under the supervision of the US Food and Drug Administration [20]. Because of its excellent therapeutic efficacies, it is one of the most widely used dietary supplements and around 75 brands of silymarin are available on the market in different dosage forms (tablets, capsules, syrups, etc.) with enhanced bioavailability under trade names such as Livergol®, Silipide®, Carsil® tablets, Legalon® capsules and Alrin-B® syrup. Nano silymarin OIC, approved by the Vietnam Drug Administration, is the only patented nanoformulation that is commercially available as a dietary supplement, in the form of capsules, for improving liver function [21,22,23].
Silymarin offers several benefits in contrast to other therapeutic agents because of its non-toxicity and excellent hydrophobic properties. It has low aqueous solubility which results in poor bioavailability. This issue can be resolved by employing a nanosystems-based approach. Nanoparticles are naturally or chemically synthesized particles that have a particle size range of 1–200 nm. Because of their small size range, they offer various advantages, such as an enhanced interaction area, enhanced aqueous solubility and intracellular permeability. In addition, they can reduce the multi-drug resistance of many anti-cancer agents, including silybin. These are distributed across the body depending upon various factors, such as their small size which aids in longer systematic circulation periods and their potential to take advantage of anti-cancer properties. They also show greater stability during storage. Nanoparticles and their use in drug delivery are a much more efficient approach for cancer treatment than traditional chemotherapy [24,25,26].
Elfaky et al. (2022) investigated the hepatoprotective potential of silymarin nanoparticles (NPs) with different particle size in Sprague Dawley adult male rats. They reported that large silver NPs are more effective in hepatoprotective action compared to small NPs [27]. Abdullah et al. (2022) designed a novel nanoformulation of silymarin-loaded chitosan NPs for improving anti-fibrotic potential against liver fibrosis. NPs were developed using the ionotropic gelation method. The authors reported that the developed formulation resulted in significant anti-fibrotic action against CCl4-induced hepatic injury [28]. Patel et al. (2022) also developed silybin-loaded NPs for inhalation with caprolactone/pluronic F68 for the treatment of lung cancer. Pharmacokinetic investigations have revealed that the developed NPs enhanced silybin bioavailability, with a more than 4-times increase in AUC in contrast to i/v administration [29]. In another study, Iqbal et al. (2022) engineered Silybum marianum-mediated biosynthesized copper oxide NPs and investigated their various biological activities, such as anti-microbial properties, catalytic properties, anti-diabetic properties, antioxidant properties and ROS/RNS inhibition. They concluded that the developed NPs have significant in vitro biological and biomedical activities. They can be employed as broad spectrum agents for various biomedical applications [30]. Finally, Staroverov et al. (2021) fabricated silymarin–selenium NP conjugates with 30–50 ± 0.5 nm particle size. The developed conjugates enhanced cellular dehydrogenase activity and facilitated its penetration into intracellular spaces [31].
It has also been reported that co-administration of silymarin with some therapeutic agents may enhance its biological activity that is reduced by the liver, such as amitriptyline, diazepam, celecoxib, fluvastatin, diclofenac, zileuton, ibuprofen, glipizide, losartan, irbesartan, piroxicam, tolbutamide, torsemide, tamoxifen and phenytoin [32]. Han et al. (2009) reported that the coadministration of different sources of silymarin with losartan significantly improved the systemic concentration of Losartan [33]. Similarly, Molto et al. (2012) examined the effect of co-administration of silymarin with darunavir and ritonavir combinations in HIV patients. They reported a decline in AUC and Cmax when co-administration of silymarin was used in combination with drugs compared to combinations of the drugs alone [34].
Considering the potential properties of silymarin, the present review has been designed to provide an insight into of its numerous pharmacological activities with detailed information about its mechanisms of action.

2. Pharmacological Aspects of Silymarin

Silymarin possesses a tremendous array of biological and pharmacological potential by interacting directly or indirectly with several molecular targets, including transcription factors, inflammatory mediators, protein kinases, receptors and enzymes, as illustrated in Figure 2.

2.1. Hepatoprotective Activity

The liver is the vital organ for metabolism of xenobiotics, lipids and numerous environmental pollutants and helps eliminate many substances from the body [35]. Silymarin has a prolonged history of traditional use in Ayurvedic medicine as a hepatoprotective agent and is nowadays broadly employed in the treatment and management of numerous hepatic disorders such as alcoholic liver disease, hepatic cancers, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and drug toxicity, as mentioned in Table 1. Numerous studies have been conducted on the potent hepatoprotective actions of silymarin and its flavonolignans in the last decade. The various proposed mechanisms through which silymarin exerts its hepatoprotective activity are represented in Figure 3. Initially, gamma-glutamyl transferase (γGT), glutamic-oxalacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT) and alkaline phosphate (ALP) are essential and characteristic enzymes of the liver, and their elevated levels indicate hepatotoxicity. Silymarin was found to decrease the levels of these hepatic enzymes and prevent cellular escape and loss of functional integrity of hepatocyte membranes. Additionally, silymarin and its flavonolignans have a significant role in the reduction of cholesterol (CH), triglyceride (TG) and low-density lipoprotein (LDL) levels along with elevation of the content of high-density lipoproteins (HDL) [36,37,38,39,40].
Oxidative stress has a critical position during the progression of NAFLD and hepatic steatosis [59], and the use of exogenous natural antioxidants such as silymarin can trigger various antioxidant enzymes and stimulate non-enzymatic nuclear factor erythroid 2-related factor 2 (Nrf2) pathways, which consequently diminishes oxidative stress [14,51,60]. Recently, Mengesha et al. (2021) evaluated the hepatoprotective effect of silymarin using a fructose-induced NAFLD rat model and concluded that silymarin significantly improves lipid profile and liver function along with amelioration of oxidative stress status [39]. Zhu et al. (2018) reported that S. marianum oil impedes oxidative stress in high-fat diet (HFD) rats by elevating the levels of endogenous antioxidant enzymes. Moreover, it was also observed that oral administration of this oil improves hepatic fatty acid synthesis and fatty acid oxidation by reducing the mRNA levels of the fatty acid synthase (FAS), the liver X receptor α and the sterol regulatory element-binding protein 1c (SREBP-1c) [50].
Along with oxidative stress, inflammation is considered to be another imperative mediator of NAFLD and NASH. Preclinical and clinical substantiations revealed that silymarin demonstrates anti-inflammatory actions via repressing the release of cytokines [51,52,53,54,57,61]. Ou et al. (2018) reported that silymarin supplementation to methionine–choline deficient (MCD) diet-induced NASH mice significantly diminishes levels of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, Interleukin (IL)-6, IL-1β and IL-12β [51]. Most of silymarin’s anti-inflammatory hepatoprotective effects have focused on cytokine release; however, Zhang et al. (2018) observed that silybin significantly impedes NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in NAFLD by elevating NAD+ levels, which as a result preserves the effect of the NAD+-dependent α-tubulin deacetylase sirtuin (SIRT)2 and restrains the activation of the acetylated α-tubulin promoted NLRP3 inflammasome, thus indicating the potential of silybin for targeting the NAD+/SIRT2 pathway [54]. Apart from its anti-inflammatory action, several studies claimed that the immunomodulatory effect of silymarin and its bio-constituents could also play a remarkable role in hepatoprotection [14,62]. The anti-apoptotic and pro-apoptotic behavior of silymarin also considerably facilitates liver protection. Indeed, elevated oxidative stress and excessive discharge of pro-inflammatory cytokines can persuade apoptosis by stimulating the c-Jun NH2-terminal kinase (JNK) signaling pathway [63]. Kim et al. (2016) also showed that silymarin administration to stressed mice attenuates JNK activation and its associated apoptotic signaling by down-regulating the expression of Bid, Bax, caspase-3 and caspase-8 as well as poly adenosine diphosphate-ribose polymerase (PARP) cleavage [53].
Various animal and cell-based studies have revealed that silymarin and its bioactive constituents significantly impair the progression of initial liver fibrosis and its associated fibrogenetic mechanisms and induce a hepatoprotective behavior. In chronic liver injury, such as hepatitis C virus (HCV) infection, fibrosis and inflammation produce fibrous scarring through the activation of myofibroblasts in the liver, which consequently exudes extracellular matrix proteins. However, the augmentation of hepatic stellate cells (HSCs) and Kupffer cells is considered as the decisive episode in the production of hepatic fibrosis [14,64]. Experimental investigations have shown that silymarin impairs the proliferation of HSCs and prevents their translation into myofibroblasts, while also down-regulating gene expression of the extracellular matrix components required during fibrosis [57,65]. In a study by Clichici et al. (2015), silymarin was reported to decrease collagen and pro-collagen III by 30% after biliary obstruction in rats [57]. Activated HSCs also display an increase in expression of the monocyte chemoattractant protein-1 (MCP-1), which is an essential chemokine responsible for controlling monocyte/macrophage movement and permeation [66,67]. Mahli et al. (2015) have affirmed that silymarin treatment down-regulates MCP-1 and collagen 1 expression upon CCl4-induced hepatotoxicity in rats [46]. Silymarin also down-regulates the expression of α-smooth muscle actin (α-SMA), which directly triggers HSCs to activate myofibroblast-like cells [42,44,57]. Furthermore, the tissue inhibitor of metalloproteinases 1 (TIMP-1) also controls the alteration of the extracellular matrix in hepatic fibrosis via MMPs [68]. Silymarin significantly improves the level of MMP-2 and prevents fibrosis [44,61,69]. Notably, Chen et al. (2012) discovered that silymarin at a dose of 100 mg/kg significantly down-regulates transforming growth factor-beta 1(TGF-β), activator protein-1 (AP-1), α-SMA, MMP-2, MMP-13, collagen-α1 (COL-α1), TIMP-1, TIMP-2 and krueppel-like factor 6 (KLF6) expressions in a thioacetamide-induced hepatotoxicity rat model [44]. Furthermore, hepatocyte apoptosis prompts HSC activation and hepatic fibrosis; noteworthy treatment with silybin also reduces these changes [51].
Kupffer cells, on the contrary, induce fibrosis via the production of Kupffer cell-derived TGF-β1, which consequently activates myofibroblasts. Moreover, Kupffer cells also regulate the synthesis of MMP and TIMPs. Silymarin also significantly obstructs activation and function of Kupffer cells [57,70]. Likewise, several other pro-inflammatory cytokines, such as leptin and resistin, act as fibrogenic markers and stimulate fibrogenesis by activating portal fibroblasts, especially HSCs. Silymarin also down-regulates the expression of these fibrogenic markers and prevents hepatic fibrosis [40,42,51,52]. The anti-inflammatory ability of silymarin to impair nuclear factor-kappa B (NF-ĸB) also remarkably retards HSC proliferation [40].
Besides the aforementioned mechanisms, silymarin and its flavonolignans also induce hepatoprotective effects by anticipating liver regeneration and blocking toxic substances. Hepatocyte regeneration significantly recovers the liver from acute and chronic damage. It has been established that silymarin administration triggers hepatic regeneration by augmenting ribosomal RNA and RNA polymerase I synthesis, which consequently stimulates protein synthesis and repairs damaged liver cells [71,72].

2.2. Anti-Diabetic Activity

Increased diabetes mellitus (DM) and its associated complications are considered a global burden. DM is a progressive metabolic disorder characterized by chronic persistent hyperglycemia, insulin resistance and impaired insulin synthesis with elevated hepatic glucose outputs [73,74]. Silymarin and its constituents have been described for their potential hypoglycemic effects, and accumulating experimental and clinical evidence suggested that silymarin extensively trims down the blood glucose level and boosts insulin secretion (Table 2 and Figure 4) [75,76,77,78,79,80,81,82,83,84].
Results from streptozotocin (STZ)-induced diabetic rat models demonstrated that silymarin, when administered orally at a dose of 80 mg/kg for 21 days, remarkably reduces HbA1c levels and fasting blood sugar (FBS) levels [77]. Silymarin also imparts potential anti-diabetic activity by impeding gluconeogenesis and glucose-6-phosphatase (G6Pase) activity [85].
Table 2. Experimental anti-diabetic activity of silymarin.
Table 2. Experimental anti-diabetic activity of silymarin.
Study ModelDose/Concentration UsedPossible Target Site/Mechanism of ActionReference
Obesity-induced insulin resistance model and HepG 2 cells30 mg/kg/day p.o. for one month
  • Elevation in SIRT1 expression
  • Decrease in Akt and FOXO1 phosphorylation
  • Increase in enzymatic activity of SIRT1
HFD model30 mg/kg/day p.o. for one month
  • Decrease in insulin resistance
  • Reduction in hepatic NADPH oxidase expression and NF-κB activity
  • Decrease in GSH, CAT and SOD activity
  • Reduction in IL-6, iNOS, NO and TNF-α levels
HFD-induced insulin resistance30 and 60 mg/kg p.o.
  • Reduction in TNF-α, IL-1β and IL-6 levels
  • Decrease in the levels of SGOT, SGPT, CH, TG and LDL
  • Decrease in insulin resistance
HFD-induced insulin resistance model and HEK293T cells40 μg/mL
50 µM
  • Reduction in FBS levels
  • Inhibition of NF-κB signaling
  • Activation of Farnesyl X receptor
Pancreatectomy model200 mg/kg p.o
  • Increase in serum insulin levels
  • Improvement in β cell proliferation
  • Elevation in Pdx1 and insulin gene expression
STZ-induced diabetes and INS1 cells50 μg/mL
2.5–100 µM
  • Decrease in FBS and increase in insulin secretion
  • Elevation in Bax and cleaved-caspase-3 protein levels
  • Reduction in Bcl-2 and pro-caspase-3 gene expression
STZ- and HFD-induced diabetes100 and 300 mg/kg p.o.
  • Decrease in hepatic glucose production
  • Increase in expression of the GLP-1 receptor in the duodenum
STZ-induced diabetes60 and 120 mg/kg/day p.o. for 2 months
  • Down-regulation of urotensin II gene expression
  • Reduction in FBS, CK-MB, LDH, MDA, CH, LDL and NO levels
STZ-induced diabetes80 mg/kg p.o. for 21 days
  • Reduction in HbA1C levels
  • Reduction in the levels of MDA, SGOT, SGPT, LDH and CK-MB in the heart
  • Decrease in the levels of CH, TG and LDL
  • An increase in Bcl-2 and decrease in Bax levels prevents apoptosis
Chronic hyperglycemia blights the mitochondrial respiratory chain and produces oxidative damage, resulting in the growth and development of DM and its associated complications. Treatment with silymarin significantly prevents oxidative damage by impeding lipid peroxidation, protein oxidation and reactive oxygen species (ROS) generation [75,91,92]. Qin et al. (2017) observed that silychristin A, one of the bioactive compounds of silymarin extracts, significantly protects ROS-induced apoptosis in INS 1 cells by elevating Bax and cleaved-caspase-3 protein levels and down-regulating Bcl-2 and pro-caspase-3 gene expressions [89]. Along with oxidative stress, inflammation is a key factor in diabetes progression and complications. Inflammatory cytokines have a decisive role in managing glucose homeostasis and insulin resistance. Any abnormal change in pro-inflammatory cytokines (IL-6 and TNF-α) could diminish insulin sensitivity and contribute to insulin resistance. In contrast, infiltrations of these cells can cause pancreatic β-cell failure [87]. Several studies have indicated that treatment with silymarin alleviates the inflammatory response by impeding the levels of NF-ĸB target genes [87,93]. It has been observed that silymarin also suppresses Interferon-γ (IFN-γ), TNF-α and IL-1β-induced nitric oxide (NO) generation, while also suppressing inducible nitric oxide synthase (iNOS) expression in pancreatic β-cells through modulating NF-κB activity and the extracellular signal-regulated kinase1/2 (ERK1/2) signaling pathway, which subsequently prevents pancreatic β-cell degradation [93].
An experiment by Xu et al. (2018) postulated that silybin decreases hepatic glucose production in STZ/high-fat diet (HFD) diabetics. Furthermore, it was observed that silybin also modulates the expression of the glucagon-like peptide (GLP)-1 receptor in the duodenum and activates neurons around the solitary tract, demonstrating the anti-diabetic potential of silymarin by eliciting the gut–brain–liver axis [90]. The Pdx1 transcription factor is believed to be directly involved in pancreatic growth and insulin gene expression, and the results from the study performed by Soto et al. (2014) revealed that silymarin elevates Pdx1 and insulin gene expression in pancreatectomized rats along with improvements in β-cell proliferation. Furthermore, it was also reported that silymarin administration up-regulates NKx6.1 gene expression, responsible for the differentiation, neogenesis and maintenance of β-pancreatic cells [94]. A current study by Feng et al. (2021) has demonstrated that silymarin administration elevates SIRT1 expression in hepatocytes [86]. Furthermore, this study, also conducted on HepG2 cells in vitro, confirmed that silymarin binds to the SIRT1 enzyme and enhances its activity, thereby indicating the potent action of silymarin on insulin resistance and gluconeogenesis [86]. Silymarin and silybin also alleviate diabetes and other related metabolic syndromes by up-regulating Farnesyl X receptor signaling when studied in vitro using HEK293T cells [79].
Furthermore, it was also observed that silybin activates the insulin receptor substrate 1/phosphoinositide 3-kinase/protein kinase B (IRS-1/PI3K/Akt) pathway, which consequently elevates insulin-mediated glucose uptake and glucose transporter-4 (GLUT4) translocation [95]. Recent studies affirmed that estrogen receptors play an essential role in glucose metabolism and preserve islet β-cell functionality and viability. Silymarin treatment significantly up-regulates the expression of both estrogen receptors α and β and protects β-cells from the progression of DM [96,97,98].
Moreover, silymarin also attenuates DM-associated complications. It has been observed that silymarin also plays an imperative role in treating diabetic-induced neuropathy, nephropathy, cardiomyopathy, hepatopathy and delayed healing [99]. Recently, Rahimi et al. (2018) reported that silymarin down-regulates urotensin II gene expression, which is responsible for diabetic-associated cardiomyopathy by causing insulin resistance, inflammation and endothelial damage [76]. Furthermore, silymarin protects cardiomyocytes against DM-induced apoptosis by elevating Bcl-2 levels and down-regulating Bax expression [77,100]. Results from Meng et al. (2019) revealed that silymarin treatment also impedes the TGF-β1/Smad signaling pathway and improves cardiac fibrosis and collagen deposition in diabetic cardiomyopathy [101].
Silymarin also displays protective effects against diabetes-induced nephropathy. It significantly attenuates oxidative stress in the renal tissues by modulating the activity of various antioxidant enzymes [102,103]. Guzel et al. (2020) reported that silymarin at a 200 mg/kg dose significantly reduces caspase activity and the levels of malondialdehyde (MDA), NO and serum creatinine, while also possessing effective renal function that protects against vancomycin-induced nephropathy in rats [104]. Chen et al. (2021) demonstrated that chronic administration of silymarin down-regulates IL-6 and intercellular adhesion molecule-1 (ICAM-1) expressions and alleviates TGF-β/Smad and JAK2/STAT3/ SOCS1 pathways using an STZ-induced diabetic nephropathy model of rats with improvements in podoxin and nephrin levels [105]. Nevertheless, clinical studies also revealed that silymarin suppresses urinary TNF-α and MDA levels, indicating protective effects against diabetes-induced nephropathy [106]. Zhang et al. (2014) reported that oral administration of silybin to STZ- and HFD-induced diabetic rats for 22 days down-regulates the expression of retinal ICAM-1, contributing to the prevention of diabetic retinopathy [107].

2.3. Anti-Cancer Activity

Cancer is a group of diseases characterized by proliferation and differentiation in the growth of abnormal cells, invading normal tissues or organs and eventually spreading to all parts of the body. Cancer is a significant public health concern, and about 19.9 million new cancer cases were diagnosed in 2020 globally and are expected to increase to 28.4 million cases in 2040 [108,109]. Plants have been used as medicines by humanity for generations, and their considerably lower toxicity, ease of availability and high specificity towards targets, compared to synthetic chemotherapeutic agents, have stimulated much interest among researchers hoping to develop plant-based anticancer drugs. Moreover, recent advancements in isolation and identification of phytochemicals have also attracted heightened attention in relation to the application of herbal medicines as a prospective target for cancer management [110,111].
Excessive investigational studies revealed that silymarin possesses anti-cancer activity against almost all types of cancers, including colorectal cancer, bladder cancer, breast cancer, gastric cancer, prostate cancer, skin cancer, lung cancer, hepatocellular carcinoma, laryngeal carcinoma, glioblastoma and leukemia, as mentioned in Table 3 and Table 4 [7,112,113]. Silymarin and its bioactive constituents can curb the rise of different tumor cells, which is achieved by cell cycle arrest at the G1/S-phase, activation of cyclin-dependent kinase (CDK) inhibitors, reduction in anti-apoptotic gene product formation, obstruction of cell survival kinases and down-regulation of inflammatory transcription factors. Moreover, silymarin can also alter the expression of gene products associated with the proliferation of different tumor cells, their invasion, metastasis and angiogenesis [7,113]. The principal mechanisms of silymarin as an anti-cancer agent are mentioned in Figure 5. Nonetheless, silymarin and its bioactive constituents are also used in the prophylaxis of numerous anti-cancer therapy-induced side effects, such as the capecitabine-induced hand-foot syndrome [114], cisplatin-induced nephrotoxicity [115,116] and radiation-induced mucositis and dermatitis [117,118,119].
Numerous observations have reported that silymarin and its bioactive constituents attenuate cellular growth and proliferation by modulating mitogen-activated protein kinase (MAPK) signaling and inducing apoptosis in vitro [133,135,147,151,158,164]. MAPK is a key signaling pathway responsible for transferring extracellular stimuli to the nucleus. MAPK is further alienated into three subtypes: (i) ERK1/2, which imperatively regulates tumorigenesis, including cellular proliferation, division and viability; (ii) JNK; and (iii) p38, which significantly controls inflammation by modulating pro-inflammatory cytokine production and cell death [167]. Singh et al. (2002) were the first to report that silybin impedes cell proliferation and stimulates apoptosis in A431 cells by inhibiting MAPK/ERK1/2 activation and up-regulating stress-activated protein kinase/JNK1/2 (SAPK/JNK1/2) and p38 MAPK [151].
It was found from in vitro studies that silymarin considerably encourages apoptosis in both A2780s and PA-1 cells by elevating Bax and diminishing Bcl-2 protein expression, along with escalating caspase-9 and caspase-3 [149]. Similarly, Vaid et al. (2015) confirmed that silymarin encourages apoptosis of human melanoma cells via the down-regulation of anti-apoptotic proteins, mainly Bcl-2 and Bcl-xl, and the up-regulation of pro-apoptotic proteins, i.e., Bax along with activation of caspases [154]. Interestingly, Yang et al. (2013) demonstrated that silybin also down-regulates survivin expression, an essential part of the inhibitors of the apoptotic protein family, which subsequently induces apoptosis of Hep-2 cells [143].
A study by Won et al. (2018) endorsed that silymarin activates death receptor 5 to persuade apoptotic cell death in HSC-4, YD15 and Ca9.22 oral cancer cell lines [146]. Interestingly, it was also explored that silybin elevates death receptor 4/5 mRNAs and TNF-related apoptosis-inducing ligand (TRAIL) mRNA expression along with activation of caspase-9, thus indicating a dual mechanism of silymarin inducing potential anti-cancer activity through the augmentation of both the extrinsic and intrinsic apoptotic pathways [131,168]. In addition to inducing an apoptotic effect, silymarin also increases the levels of ceramides and modulates the secretion of micro RNA (miRNA) by down-regulating miR-92-3p and up-regulating miR223-3p and miR16-5p, which usually act as oncogenes and tumor suppressors in carcinogenesis [138]. Most importantly, Zhang et al. (2015) concluded that silybin prevents glioma cell proliferation and induces apoptosis via impeding PI3K and Forkhead box M1 9 (FoxM1) expression, which further triggers the mitochondrial apoptotic pathway [169].
Furthermore, preventing cellular proliferation by disrupting typical cell cycle sequences and cellular divisions at various cell cycle stages is an important mechanistic approach to inducing anti-tumor activity. Cyclins, CDKs and cyclin-dependent kinase inhibitors (CDKIs) are critical cell cycle regulators which are overexpressed during cancer. Under normal physiological conditions, CDKs regulate the expression of genes involved in cell cycle transition. CDK2 with cyclin E and cyclin A, and CDK4 and 6 with cyclin D (CD), control G1/S cell cycle transition, whereas Cdc2 kinase with cyclin B regulates G2/M transition [159,170,171]. Silymarin and its bioactive flavonolignans significantly inhibit over-expression of these regulators and induce anti-carcinogenic activity [132,141,149,156]. It was observed from Western blot studies that silymarin impedes, in a dose-dependent manner, the gene expression of CD1 and CD2 along with a noteworthy diminution in protein expression of various CDKs in A375 cells. However, the levels of the CDK inhibitory proteins, Kip1/ p27 and Cip1/p21, were elevated after silymarin treatment [154]. Eo et al. (2015) reported that silymarin inhibits proliferation in HCT116 and SW480 cells by triggering the proteasomal degradation of CD1 at threonine-286 [132]. Moreover, Fan et al. (2014) demonstrated that silymarin dose-dependently inhibits the G1/S transition phase of the cell cycle in A2780s and PA-1 ovarian cancerous cells by altering CDK2, p53, p21 and p27 gene expressions [149]. Notably, a clinical study revealed that silymarin treatment in hepatocellular carcinoma patients also arrests the cell cycle pathway by down-regulating expression of the DNA topoisomerase 2-binding protein 1 (TOPBP1), the nucleolar and spindle-associated protein 1 (NUSAP1) and the cell division cycle-associated 3 protein (CDCA3), which are important for mitotic progression and regulation [172].
Despite inhibiting various CDK and MAPK signaling pathways, silymarin also significantly impedes various other pathways, such as the Notch pathway [141], the PI3K-PKB/Akt signaling pathway [120], the PP2Ac/ AKT Ser473/ mammalian target of rapamycin (mTOR) pathway [134], the Slit-2/Robo-1 signaling pathway [140,150] and the Wnt/β-catenin signaling pathway [129]. The PI3K/Akt pathway is an essential regulatory element responsible for cellular growth, proliferation and differentiation through activation of CDK-4 and CDK-2. Feng et al. (2016) reported that silybin impedes the PI3K/Akt/mTOR signaling pathway in U266 cells by down-regulating the protein expression of p-Akt, PI3K and p-mTOR [157]. Furthermore, it was shown that inhibition of PI3K/Akt pathways also restrains bladder cancer growth and progression in T24 and UM-UC-3 human bladder cancer cells [120]. The β-catenin-dependent Wnt signaling (Wnt/β-catenin signaling) pathway is also accountable for cellular proliferation, apoptosis and tissue homeostasis [173,174]. Numerous in vitro studies demonstrated silymarin anti-cancer activity via modulation of this signaling pathway [129,152]. Vaid et al. (2011) reported that silymarin treatment to A375 and Hs294t cells up-regulates expression of the glycogen synthase kinase-3β (GSK-3β) and the casein kinase 1α (CK1α), subsequently resulting in β-catenin phosphorylation and blockage of cellular migration and invasion [152]. Later on, Lu et al. (2012) observed that silymarin also modulates gene expression of the lipoprotein receptor-related protein 6 (LRP6), a critical co-receptor for the Wnt/β-catenin signaling pathway [129]. Notch 1 signaling directly activates the cyclooxygenase-2 (COX-2)/Snail/E-cadherin pathway, which subsequently induces cancerous cell invasion and migration; however, silymarin’s ability to down-regulate Notch1 prevents this cellular invasion and results in decreased cancer growth [141,175].
Matrix metalloproteinases (MMPs) degrade extracellular matrices and are accountable for metastasis and migration of cancerous cells in carcinogenesis. Silybin was reported to significantly impede MMP-2 gene expression by modulating Janus kinase-2/signal transducers and activators of the transcription-3 (Jak2/STAT3) pathway [126]. MMP plays a pivotal role in cancer metastasis, together with AP-1, through stimulation of the epithelial to mesenchymal transition of tumor cells. Down-regulating AP-1 may also serve as a possible remedial approach for cancer treatment [176]. It was reported that silybin acts as a potential anti-metastasis agent by remarkably suppressing cellular invasion by impeding AP-1 dependent MMP-9 gene expression in MCF-7 human breast carcinoma cells [127]. Recently, Si et al. (2020) found that silybin treatment elevates mitochondrial fusion through an increase in the expression of mitochondrial fusion-associated proteins (optic atrophy 1, mitofusin 1 and mitofusin 2) and down-regulation of the expression of the mitochondrial fission-associated protein (dynamin-related protein 1 (DRP1)) in MDA-MB-231 breast cancer cells, which consequently impedes cellular migration [124]. Furthermore, it was observed that silybin treatment also abolishes activation of the NLRP3 inflammasome through repression of ROS generation, resulting in reduced tumor cell migration and invasion [124]. The C-X-C chemokine receptor type in cancer cells is accountable for tumor growth, proliferation and angiogenesis [177]. Kacar et al. (2020) demonstrated that silymarin activates SLIT2 protein and suppresses C-X-C chemokine receptor type 4 expressions in DU-155 cells, thereby reducing tumor proliferation and metastasis in prostate cancer [150].
The vascular endothelial growth factor (VEGF) displays a significant role in tumor-induced angiogenesis and can be used as a hopeful target for anti-cancer therapy. Western blotting analysis demonstrated that a 500 mg/kg silymarin treatment given to mice remarkably down-regulated VEGF protein expression in the A375 tumor xenografts model [154]. Furthermore, silymarin administration was also reported to reduce CD31 expression levels, contributing to the development of new vasculature. Most interestingly, Khan et al. (2014) revealed that 9 mg/mouse topical applications of silybin significantly repress tumorigenesis and oxidative stress by down-regulating iNOS, NO, TNF-α, IL-6, IL-1β, COX-2 and NF-κB [153]. Nowadays, drug resistance to cancer therapies is a major problem in combating this disease, and various studies affirm that feedback activation of STAT-3 is majorly responsible for mediating drug resistance. However, considerable evidence suggests that silymarin can reverse STAT-3-associated cancer drug resistance by down-regulating its gene expression [178].

2.4. Neuroprotective Activity

Silymarin and its flavonolignans are also involved in the treatment of various neurogenerative diseases and attenuation of the neurodegenerative alteration developed after cerebral ischemia. The main neuroprotective mechanisms of silymarin are illustrated in Figure 6. Kittur et al. (2002) demonstrated silymarin’s neurotrophic and neuroprotective effects via augmentation of nerve growth factor (NGF)-mediated neurite outgrowth in PC-12 neural cells and protection against oxidative stress-triggered cell death in rat hippocampal neurons [179]. Nitrosative stress, oxidative stress and neuroinflammation are indeed imperative pathological traits of various neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases [112,180]. Silymarin treatment significantly suppresses neuronal oxidative stress and neuroinflammation by increasing numerous exogenous enzymatic activities and attenuating inflammatory responses, respectively, as discussed in Table 5 [181,182,183,184,185,186,187]. Recently, it was also observed that silymarin intake prevents glutamate release via inhibition of voltage-dependent Ca2+ channels and the ERK1/2 pathway in a rat model of kainic acid-mediated excitotoxicity [188].
Parkinson’s disease is the most common neurodegenerative disorder and is characterized by progressive loss of dopaminergic neurons with pervasive intracellular aggregation of the α-synuclein protein in the substantia nigra pars compacta causing irregularities in motor behavior [189,190]. Silymarin displays potential anti-Parkinson activity by upholding striatal dopamine levels via inhibition of apoptosis and protection of dopamine neurons in the substantia nigra [191,192]. Srivastava et al. (2017) reported that silymarin treatment reduces α-synuclein protein levels through modification in mRNA expression of various α-synuclein suppressive genes in a Caenorhabditis elegans transgenic model [193]. Moreover, silymarin’s ability to hamper monoamine oxidase-B (MAO-B) enzymatic activity adds to the neuroprotective mechanisms of silymarin which counteract the loss of dopamine in parkinsonism [194,195]. Most importantly, Wang et al. (2002) observed that silymarin remarkably prevents microglia (glial cell) activation by inhibiting NF-κB signaling, which furthermore impairs dopamine neuron damage and likely represents a possible mechanism for its neuroprotective activity [196]. Silymarin treatment also augments the expression of the lysosome-associated membrane protein-2 (LAMP-2A) protein and reduces p-AMPK-mediated Ulk1-dependent macroautophagy in the MPTP-induced Parkinson model [197].
Alzheimer’s disease is a progressive neurodegenerative disease exemplified by progressive amyloid-beta (Aβ) peptide aggregation, synapse and nerve destruction and acetylcholine deficiency, causing memory impairment along with functional and behavioral alterations [112,198]. Inhibition of Aβ aggregation and its associated oxidative stress, as well as acetylcholinesterase (AChE) activity, is a prospective beneficial approach that can slow or diminish the development of Alzheimer’s disease [112]. Various in vivo and in vitro experimental studies affirm that silymarin and its bioactive constituents display anti-amyloidogenic activities and are capable of impairing Aβ fibril formation and aggregation along with inhibition of AChE enzymatic activity [198,199,200,201,202]. The amyloid precursor protein (APP) is liable for the formation of Aβ peptides through its sequential proteolytic cleavages and has a central role in the growth of Alzheimer’s disease [203]. Yaghmaei et al. (2014) demonstrated that silymarin remarkably down-regulates APP gene expression [201]. Furthermore, it was also found that silymarin reduces Aβ-protein fibril formation in an APP transgenic animal model, indicating the role of silymarin in the inhibition of APP expression [200,202]. Oxidative stress is also extremely accountable for Aβ toxicity and displays a critical role in the pathophysiology of Alzheimer’s disease. Silymarin was found to have a protective effect against Aβ-mediated oxidative stress [199,204,205]. Zhou et al. (2016) reported that isosilybin attenuates oxidative stress-induced Aβ peptide formation in hippocampal neuronal cells, possibly via augmentation of the NRF2/ARE signaling pathways [205]. Recently, it was also found that estrogen receptors play a significant role in protection against Aβ-induced toxicity, and treatment with silymarin notably modulates estrogen receptor activity and its related signaling pathways, such as MAPK and PI3K-Akt [206,207].
Table 5. Experimental studies demonstrating the activity of silymarin on CNS.
Table 5. Experimental studies demonstrating the activity of silymarin on CNS.
Pharmacological ActivityStudy ModelDose/Concentration UsedPossible Target Site/Mechanism of ActionReferences
NeuroprotectiveLipopolysaccharide (LPS)-induced neuroinflammatory impairment25–100 mg/kg
  • Over-expression of BDNF and TrkB genes
  • Reduction in IL1β, NF-ĸB and TNF-α expression
Docetaxel-induced central and peripheral neurotoxicities25 and 50 mg/kg
  • Down-regulation of NF-ĸB, TNF-α, Bax and JNK expression
  • Up-regulation of Nrf2, Bcl-2, CREB and HO-1 expression
  • Reduction in the levels of GSH and SOD
STZ-induced diabetic neuropathy30, 60 mg/kg/day p.o.
  • Reduction in the levels of SGPT, SGOT, INFγ, IL-1β, IL-6, TNF-α, TBRAS and endogenous antioxidant enzymes
  • Increase in the levels of TP and albumin
30–300 g/mL
  • Inhibition of MAO-B and activation of Na+/K+-ATPase
Manganese-induced neurotoxicity100 mg/kg/day i.p.
  • Reduction in AOPP, PCO, TBARS and NO levels in the cerebral cortex
  • Elevation in antioxidant enzyme activities
Acrylamide-induced cerebellar damage160 mg/kg
  • Elevation in 5-HT and dopamine levels
  • Reduction in MDA levels
  • Increase in CAT and SOD levels
Ischemic surgery 200 mg/kg
  • Postponement of neuronal cell death
Kainic acid (KA)-induced excitotoxicity50–100 mg/kg
  • Suppression of synaptosomal glutamate release
  • Inhibition of ERK1/2 activity
  • Blockage of voltage-gated Ca2+ channels
Middle cerebral artery occlusion
  • Amplification of pAkt, HIF-1α, pmTOR and Bcl-2 expression
  • Down-regulation of Bax and NF-κB expression
  • Activation of the Akt/mTOR signaling pathway
Anti-Alzheimer1–42-induced Alzheimer’s 70 and 140 mg/kg p.o. for 4 weeks
  • Inhibition of amyloid plaque formation
  • Down-regulation of APP gene expression
APP transgenic mice and PC12 cells0–100 µM
  • Decrease in A β-protein fibril formation
  • Improvement in behavioral abnormalities
APP/PS1 transgenic mice2–200 mg/kg/day
  • Inhibition of AChE activity
  • Reduction in plaque formation
Scopolamine-induced dementia 200–800 mg/kg p.o. for 2 weeks
  • Diminution in AChE activity and MDA level
  • Restoration of dopamine and GABA activity
  • Down-regulation of GFAP and NF-κB protein expression
1–42-induced Alzheimer25–100 mg/kg
  • Modulation of estrogen receptor α and β expression
  • Inhibition of MAPK and PI3K-Akt pathways
Aluminum chloride (AlCl3)-induced Alzheimer’s34 mg
  • Suppression of AChE activity
25–35-induced Alzheimer’s25–100 mg/kg
  • Elevation in autophagy level
  • Decrease in COX-2, NF-κB and iNOS expression
  • Elevation in IL-4 levels
Aβ25–35-induce oxidative stress damage in HT-22 cells
  • Activation of the NRF2/ARE pathway
Anti-ParkinsonCaenorhabditis elegans transgenic model24.12 µg/mL
  • Decrease in α-synuclein protein levels
  • Alteration in mRNA expression of α-synuclein suppressive genes
  • Elevation in dopamine levels
MPTP-induced parkinsonism40 mg/kg i.p. for 2 weeks
  • Decrease in beclin-1, α-synuclein, sequestosome, p-Ulk1 and p-AMPK levels
  • Elevation in DA, LAMP-2 and p-mTOR levels
6-OHDA-induced neurodegeneration and parkinsonism100 and 200 mg/kg i.p.
  • Inhibition of TBARS formation
  • Protection of substantia nigra
6-OHDA-induced neurodegeneration and parkinsonism100, 200 and 300 mg/kg, i.p. for 5 days
  • Improvement in motor coordination
  • Elevation in MDA levels
  • Reduction in CSF level of IL-1β
MPTP-induced parkinsonism20–400 mg/kg, i.p.
  • Preservation of dopamine level and dopamine neurons in the substantia nigra
  • Reduction in apoptotic cells
Anti-depression5–200 mg/kg
  • Elevation of NO levels
Olfactory bulbectomized (OBX) technique100–200 mg/kg
  • Improvement in BDNF expression
  • Reduction in MDA, IL-6, TNF-α levels and oxidative stress
  • Elevation of dopamine levels
Reserpine-induced depression0–400 mg/kg
  • Up-regulation of BDNF and TrkB expression
  • Improvement in neuronal stem cell proliferation
  • Enhancement in p-ERK and p-CREB levels
1–42-induced Alzheimer’s25–100 mg/kg
  • Enhancement in BDNF and TrkB expression
Apart from its effect on various neurodegenerative disorders, silymarin and its constituents also help manage depression. Depression is a mood disorder characterized by an importunate feeling of unhappiness and loss of interest and is directly allied with brain-derived neurotrophic factors (BDNF) and neuroinflammation [112]. Indeed, BDNF is a neurotrophin neuronal growth, function and survival factor, and impairment in BDNF/ tropomyosin receptor kinase B (TrkB) signaling is considered a potential underlying factor for depression [216,217]. Several experimental studies demonstrated that silymarin and its associated constituents elevate BDNF levels, and also impair inflammatory responses and oxidative stress, via amplification of the BDNF/TrkB pathway [183,184,214,215]. In addition to this, a study by Khoshnoodi et al. (2015) has revealed that silymarin’s capability to elevate NO levels modulates the effect of various neurotransmitters, such as serotonin, norepinephrine and dopamine, which consequently induces antidepressant-like effects [213].
Silymarin was also found to ameliorate cerebral ischemia and cerebral stroke by interrupting neurodegenerative progression and inhibiting neuronal cell death in several ischemia models [211,218,219]. Wang et al. (2012) observed that silybin treatment before permanent middle cerebral artery occlusion significantly activates the Akt/mTOR signaling pathway and induces protection against ischemic stroke. Furthermore, it was affirmed that silybin also up-regulates hypoxia-inducible factor 1α (HIF-1α) and Bcl-2 expression and down-regulates Bax and NF-κB expression in ischemic brain tissue after stroke [212].

2.5. Cardioprotective and Anti-Hypertensive Activity

Cardiovascular diseases are currently the foremost source of fatality in aged adults and are usually allied with ischemic injury [112]. However, their increasing prevalence has warranted the attention of researcher who are now seeking to generate newer solutions to curb this problem and promote cardiac health. In this regard, various in vitro and in vivo studies have been carried out that describe the cardioprotective effects of silymarin, which directly plummets the levels of MDA, lactate dehydrogenase (LDH), troponin C and creatine kinase-MB (CK-MB), which are important cardiac biomarkers [77,220,221]. Moreover, silymarin treatment also diminishes myocardial oxidative stress by elevating catalase (CAT) and superoxide dismutase (SOD) activities as well as GSH content in the heart [222]. Apart from reducing the level of cardiac enzymes, silymarin also protects the heart by arresting cardiomyocyte apoptosis. Taghiabadi et al. reported that silymarin decreases the Bax/Bcl-2 ratio, cytosolic cytochrome c content and cleaved caspase-3 levels of the heart [222]. Later on, a study by Alabdan (2015) also showed that pre-treatment with 80 mg/kg of silymarin orally could prevent hyperglycemia and myocardial injury in STZ-treated diabetic rats [77].
Notably, silymarin intake in CCl4-intoxicated rats markedly decreases the level of VEGF, which is an important angiogenic biomarker. Furthermore, it was observed that silymarin ameliorates the level of inflammatory and immunological biomarkers, such as TNF-α, InFγ, IL-6 and C-reactive protein (CRP), and marks the anti-inflammatory potency of silymarin in protection against myocardial injury [220]. Gabrielová et al. (2015) observed that 2,3-dehydrosilybin, a constituent of silymarin, remarkably increases luciferase gene expression and intracellular cAMP levels while also inducing inhibition of the phosphodiesterase enzyme in isolated neonatal rat cardiomyocytes [223].
Besides this, silymarin also plays a critical role in reducing elevated atrial blood pressure (B.P.). Silymarin significantly reduces systolic B.P., basal arterial B.P. and heart rate in both the DOCA salt and fructose-induced hypertension model. It was also observed that silymarin treatment in hypertensive rats decreases urinary K+ excretion and tribarbituric acid reactive substance (TBARs) levels along with an augmentation in urinary Na+ excretion and endogenous antioxidant enzyme levels, as mentioned in Table 6 [224,225].

2.6. Anti-Viral Activity

Viral infections are considered a menace to public health and enhance the global socioeconomic burden. Currently, the significant increase of viruses as human pathogens and the rise of large-scale epidemic outbreaks have highlighted a demand for new anti-viral drugs. Silymarin depicts inhibitory action against many viruses in various cell lines and in vivo studies by targeting manifold steps of the viral life cycle, as discussed in Table 7. Silymarin and silybin directly hinder infection of the hepatitis C virus (HCV) in cell cultures by blocking viral entry, viral fusion, viral RNA and viral protein synthesis along with polymerase activity and virus transmission [56,226,227,228,229]. Silymarin may reveal an advantageous relationship with viral hepatitis through its inhibitory potential on inflammatory processes and the cytotoxic cascade of events triggered by viral replication [230,231]. Polyak et al. (2007) reported that, besides impairing HCV RNA and protein expression to prevent viral replication, silymarin also inhibits TNF-α secretion and NF-ĸB-dependent transcription, thus indicating the dual anti-viral and anti-inflammatory activity of this extract [232]. Furthermore, data suggest that certain bioactive components of silymarin significantly inhibit HCV infection via modulating the Jak-STAT pathway. Moreover, an in vivo study using the uPA+/+/SCID+/+ chimeric mice model by DebRoy et al. (2016) concluded that intravenous (iv) monotherapy with silybin significantly inhibits HCV production and prevents the production of various transcription regulators and inflammation-related cytokines [233].
In another work, Blaising et al. (2013) demonstrated that both silybins A and B significantly block HCV entry into the cell through clathrin-coated pits and vesicles by slowing HCV endosomal trafficking and inhibiting clathrin-mediated endocytosis, thereby preventing HVC infection [234]. Consistent with the above results, it was also demonstrated that oral concomitant treatment of silybin–vitamin E–phospholipid complex pills with PEG-IFN and ribavirin in chronic hepatitis patients for 12 months significantly lowers the viral load [235,236]. Furthermore, iv infusion of silymarin also displayed significant anti-HCV activity in clinical studies [229,237]. HCV-associated liver cirrhosis and liver carcinoma are common after liver transplantation. Clinical data also reported that silymarin and its bioactive constituents prevent HCV reoccurrence after liver transplantation [238,239].
As in HCV infection, silybin also hinders clathrin-mediated endocytosis in the hepatitis B virus (HBV), thus inhibiting HBV entry into cells [240]. Apart from its anti-hepatitis potential, silymarin possesses an anti-viral activity against other viral infections, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [241], the influenza virus [242,243], the dengue virus [244,245], the mayaro virus [246,247], the enterovirus 71 [248], the chikungunya virus [249,250], the herpes virus [251] and the human immunodeficiency virus (HIV) [252,253], by similarly inhibiting viral entry, viral fusion, viral RNA and viral protein synthesis. Some studies revealed that silymarin impairs influenza replication dose-dependently via inhibition of mRNA synthesis [242,243]. Interestingly, the 23-(S)-2-amino-3-phenylpropanoyl derivative of silybin also blocks viral replication by impeding formation of the Atg5-Atg12/Atg16L complex and amplifying infection-induced autophagy. In addition, this silybin derivative also improves MAPK/ERK/p38 and IkB kinase (IKK) signaling pathways [243].
Table 6. Experimental studies demonstrating the effect of silymarin on the cardiovascular system.
Table 6. Experimental studies demonstrating the effect of silymarin on the cardiovascular system.
Study ModelDose/Concentration UsedFinding/Possible Mechanism of ActionReference
CCl4-induced cardiomyopathy200 mg/kg/day p.o. for 21 days
  • Reduction in CK-MB, Troponin-T, INFγ, IL-6, TNF-α, CRP and VEGF levels by silymarin
Ischemia reperfusion-induced myocardial infarction100–500 mg/kg p.o. for one week
  • Significant decrease in the levels of MDA, SGOT, SGPT, LDH, CK-MB, CK and endogenous antioxidant enzymes.
Acrolein-induced cardio toxicity25–100 mg/kg p.o.
  • Significant decrease in the levels of MDA, troponin T, CK-MB and endogenous antioxidant enzymes
  • Inhibition of apoptosis by a reduction in the Bax/Bcl-2 ratio, cytosolic cytochrome c content and cleaved caspase-3 levels in heart
Isoproterenol-treated rat cardiac myocytes0–0.7 mM
  • Reduction in SOD, LDH and MDA levels
  • Up-regulation of SIRT1 and Bcl-2
Perfused adult rat heart model and H9c2 cells0.01–10 µM
  • Elevation in luciferase gene expression and intracellular cAMP levels
  • Inhibition of phosphodiesterase enzyme
Doxorubicin-induced cardio toxicity and hepatotoxicity60 mg/kg p.o. for 12 days
  • Decrease in the level of SGOT, SGPT, LDH, CK-MB and endogenous antioxidant enzymes
DOCA salt-induced hypertension 300 mg/kg and 500 mg/kg, p. o. for 4 weeks
  • Decrease in systolic B.P., basal arterial B.P. and heart rate
  • Elevation in urinary Na+ excretion and endogenous antioxidant enzymes levels
  • Reduction in urinary K+ excretion and TBARS levels
Fructose-induced hypertension 300 mg/kg and 500 mg/kg, p. o. for 6 weeks
  • Decrease in systolic B.P., basal arterial B.P. and heart rate
  • Elevation in endogenous antioxidant enzymes levels
  • Reduction in TBARS levels
Table 7. Experimental anti-viral activity of silymarin.
Table 7. Experimental anti-viral activity of silymarin.
Type of Viral InfectionStudy ModelDose/Concentration UsedPossible Target Site/Mechanism of ActionReference
Chikungunya virusVero and BHK-21 cells50 μg/mL
  • Reduction in viral replication efficacy
  • Down-regulation of the production of viral proteins involved in the replication
HCVHuh 7 cells
  • Inhibition of NS5B RNA-dependent RNA polymerase activity
  • Inhibition of HCV and JFH1 replication
HepG2 and Huh 7 cells
  • Reduction in JFH-1RNA and HCV RNA production
  • Inhibition of MTP-dependent apoB secretion
Huh 7 and PBM cells20–200 μg/mL
  • Stimulation of the Jak-Stat pathway
  • Inhibition of TNF-α secretion and NF-ĸB-dependent transcription
  • Inhibition of HCV RNA and protein expression
Huh7.5 cells10.4–150 µM
  • Inhibition of the clathrin-dependent pathway by inhibiting HCV endosomal trafficking and clathrin-mediated endocytosis
1–1000 µM
  • Inhibition of the HCV NS4B protein
uPA+/+/SCID+/+ chimeric mice model61.5, 265 and 469 mg/kg i.v. for 14 days
  • Decline in HCV production
  • Elevation in anti-inflammatory and anti-proliferative gene expression
Influenza virusMDCK cells100 μg/mL
  • Inhibition of mRNA synthesis
MDCK, A549 and Vero cells
Viral infection of BALB/c mice
25 mg/kg/day
  • Activation of MAPK/ERK/p38 and IKK signaling pathways
  • Inhibition of viral replication and formation of the Atg5-Atg12/Atg16L complex
  • Enhancement in infection-induced autophagy
HIVPBMC and CEM-T4 cells50–500 µM
  • Inhibition of T cell mitochondrial respiration and glycolysis
  • Inhibition of HIV entry
TZM-bl, PBMC and CEM cells40–324 µM
  • Inhibition of viral replication
  • Reduction in CD4+, CD8+ and CD19+ T cell proliferation
  • Blockage of activation markers on CD4+ T cells
Mayaro virusHepG2 cells3.125–1400 μg/mL
  • Decrease in MDA levels and ROS formation
HBVHepG2-NTCP-C4 cells0–200 μM
  • Inhibition of clathrin-mediated endocytosis and reduction in transferrin uptake
Herpes virusVero cell 0–125 μg/mL
  • It reduced the IC50 value to 100 μg/mL
SARS-CoV-2Human umbilical vein endothelial cells5–25 µM
  • Down-regulation of TNF-α, IL-6, MCP-1 and PAI-1 gene expressions
1–100 µM
  • Inhibition of Mpro (main protease)
Importantly, silymarin exerts its anti-HIV activity by modulating various cellular functions that are responsible for T cell activation and proliferation. Silymarin significantly reduces CD4+, CD8+ and CD19+ T cell proliferation and blocks activation markers such as HLA-DR, CD38, CCR and Ki67 on CD4+ T cells, which consequently results in fewer CD4+ T cells expressing the HIV co-receptors (the C-X-C chemokine receptor 4 and the C-C chemokine receptor 5) [252]. Furthermore, another study by McClure et al. (2014) demonstrated that silymarin disturbs T cell metabolism by impairing mitochondrial respiration and glycolysis, which is useful in combating HIV infection while simultaneously blocking viral replication [253]. Moreover, based on the dual potential of silymarin to prevent both HCV and HIV viral replication, many clinical trials have been performed using this bioactive drug for HCV/HIC coinfected patients [258,259,260]. Recently, in line with the above results, many clinical trials are underway to study and understand the potential prophylactic or therapeutic activity of silymarin and its bioactive flavonolignans against COVID-19 [13,241,257,261,262].

2.7. Photoprotection and Dermal Applications

Skin is the outermost protective organ of the human body, defending it from oxidants and several exogenous pollutants [263,264]. Ultraviolet (UV) radiation-induced ROS generation modulates several cellular pathways and the expression of various inflammatory cytokines that, consequently, alter epidermal cellular activity. Moreover, elevated collagenase, elastase and hyaluronidase enzymatic activities also result in photoaging [265]. Accumulating data divulged that silymarin and its bioactive compounds have a pivotal role in skincare and can be used to treat various skin disorders such as melasma, photo-aging, rosacea, atopic dermatitis, psoriasis, acne and radiodermatitis, as mentioned in Table 8 and Table 9.
DNA mutation and the generation of cyclobutane pyrimidine dimers (CPDs) are the common mechanisms that explain the photo-protective activity of silymarin, though it was recently reported that silymarin also repairs UVB-induced DNA damage by augmenting the expression of various nucleotide excision repair (NER) genes [266,267]. In XPA-deficient and XPA-proficient mice models, silymarin treatment remarkably reduces sunburn/apoptotic cell counts in NER-proficient mice. However, no significant change was observed in their wild-type counterparts, thus confirming the role of NPR gene expression in silymarin-mediated photoprotection [267]. Adjacent to the NER pathway, the p53 signaling pathway plays a crucial role in photoprotection. Several experimental studies have established that up-regulation of p53-mediated growth arrest and DNA damage-inducible protein α (GADD45α) expression is a decisive mechanism by which silymarin protects against UVB-induced photo damage [266,268,269]. GADD45α is indeed a vital transcription factor that is mediated by p53 and which regulates apoptosis, cellular proliferation and DNA damage repair [270,271]. Additionally, Rigby et al. (2017) determined the role of p53 in UVB photoprotection using p53 heterozygous (p53+/) and p53 knockout (p53/) mice. Results revealed that silybin treatment considerably reduces UVB-induced lesions in p53+/+ compared with p53 deficient mice, affirming the role of silymarin in photoprotection via p53 activation [269]. Moreover, an earlier study by Gu et al. (2005) reported that silymarin hampers JNK1/2, ERK1/2, MAPK/p38 and AKT signaling pathways during UV-induced mitogenesis and prevents skin from light damage [272]. Silymarin and its major constituents can also induce photoprotection by preventing DNA single-strand break (SSB) formation and ROS generation along with a decrease in the levels of HSP70, MMP-1 proteins and caspase-3 activation [273,274].
The anti-inflammatory, antioxidant and anti-apoptotic potential of silymarin also has a significant role in photoprotection and impairing UV-induced oxidative stress [275,276,277,278]. Juráňová et al. (2019) showed that silymarin attenuates skin inflammation by activating NF-κB and AP-1 through up-regulation of IL-8 mRNA, which consequently protects from UVB-induced light damage [279]. Silymarin also significantly prevents UV-induced apoptosis by impairing caspase-3 and 8 activity [280,281].
Table 8. Experimental studies demonstrating the dermal applications of silymarin.
Table 8. Experimental studies demonstrating the dermal applications of silymarin.
Pharmacological ActivityStudy ModelDose/Concentration UsedPossible Target Site/Mechanism of ActionReference
Photo protectiveUV exposure0.1–0.2 mg/mL/kg topically
  • No skin irregularity, erythema, hyperpigmentation or edema were observed
UV exposure
  • Impedes SSB production and ROS generation
  • Decreases HSP70, MMP-1 and caspase-3 level
  • Increases HO-1 level
UV exposure in HaCaT cells75 μm
  • Decrease in caspase-3 activation and ROS levels
  • Up-regulation of CHOP protein expression
UVB-induced skin damage in human dermal fibroblasts1.6–100 μM
  • Decrease in caspase-3 activation and ROS levels
XPA-deficient mice, XPA-deficient and XPA-proficient human fibroblasts and normal human epidermal keratinocytes10 and 20 µg/mL
  • Reduction in apoptotic cell count
  • Up-regulation of NPR gene expression
JB6 cells and mouse skin100 μm
  • Impediment of cell cycle progression
  • Up-regulation of GADD45α gene expression
Human dermal fibroblasts100 μm
  • Elevation in p53 and GADD45α gene expressions
SKH-1 hairless mouse9 mg topically
  • Activation of the p53 pathway
SKH-1 hairless mice skin9 mg topically
  • Reduction in MAPK and AKT signaling pathways
  • Elevation in the p53 signaling pathway
Anti-alopeciaHuman dermal papilla cells0–200 μM
  • Elevation in luciferase enzymatic activity
  • Activation of the AKT and Wnt/β-catenin signaling pathway
Wound healingHuman fibroblast cells4.5–36 µg/mL
  • Down-regulation of COX-2 mRNA expression
Rat wound model with full-thickness excision2% ointment containing 500 mg silymarin
  • Reduction in redness, swelling and exudation
  • Decrease in MDA levels
  • Elevation of NO synthase expression and estradiol levels
Rat wound model full-thickness cutaneous defect6–12 mg/mL
  • Decrease in lymphocyte and macrophage counts
  • Elevation in fibrocytes count, college fibers and fibroblasts
  • Improvement in tensile strength
Normal human dermal fibroblasts
  • Up-regulation of IL-8 mRNA
  • Activation of NF-κB and AP-1
  • Reduction in IL-6 and IL-8 release
Anti-aging0.01–2.5 g/L
  • Inhibition of collagenase and elastase enzyme activities
Table 9. Clinical evidence published in the previous 10 years depicting various pharmacological activities of silymarin.
Table 9. Clinical evidence published in the previous 10 years depicting various pharmacological activities of silymarin.
DiseaseNo. of PatientsDose; DurationAdd on TherapyStudy OutcomesReference
Diabetes40140 mg tid p.o.; 90 days
  • Decrease in FBS, HbA1c, MDA, CH, TG and LDL
40140 mg tid p.o.; 45 days
  • Reduction in FBS, SOD, MDA and hs CRP levels
40420 mg tid p.o.; 45 days
  • Reduction in HOMA-IR, insulin, LDL CH and TG levels
  • Increase in HDL levels
85 (diagnosed with Type 1 diabetes) 105 mg bid p.o.; 6 monthsBerberis aristata 588 mg
  • Reduction in FBS, HbA1c, LDL CH and TG levels
  • Increase in HDL levels
691000 mg/day p.o. Berberine 210 mg/day
  • Decrease in FBS, HbA1c, SGPT, SGOT, CH, TG and LDL levels
Dyslipidemia139 105 mg bid p.o.; 6 monthsBerberis aristata 500 mg and Monacolin K 10 mg
  • Reduction in FBS, LDL CH and TG levels
  • Inhibition of TNF-α and IL-6 release
137 105 mg bid p.o.; 6 monthsBerberis aristata 588 mg
  • Reduction in FBS, insulin and HOMA-index levels
  • Improvement in lipid profile
105105 mg bid p.o.; 3 monthsBerberis aristata 588 mg
  • Reduction in retinol-binding protein-4 and resistin levels
  • Increase in adiponectin levels
Melasma (skin disorder) 967 and 14 mg/mL cream bid topically; 4 weeks
  • Melasma area and severity index (MASI) reached zero after 4 weeks
Acne 201% seed oil cream bid topically
  • Reduction in facial wrinkles and improvement of skin tone
56N-acetylcysteine and Selenium
  • Reduction in MDA and IL-8 levels
  • Decrease in the number of inflammatory lesions
Hepatocellular carcinoma40
  • Reduction in CDCA3, TOPBP1 and NUSAP1 levels
Cisplatin-induced nephrotoxicity60140 mg bid p.o.; 7 days
  • Decrease in BUN and creatinine levels
86140 mg tid p.o.; 21 days
  • Decrease in serum creatinine levels
Capecitabine-induced hand-foot syndrome40 (diagnosed with G.I.T. cancer1% gel bid topically; 9 weeksCapecitabine
  • Minimizes the severity of the syndrome and impairs its incidence
Radiotherapy-induced mucositis27 (Diagnosed with head and neck cancer)420 mg/ day p.o.; 6 weeks
  • Significant delay in mucositis growth and progression
Radiation-induced dermatitis40 (Diagnosed with breast cancer)1% gel bid topically; 5 weeks
  • Significant delay in dermatitis growth and progression
NAFLD 81 280 mg bid p.o.; 90 daysVitamin C 120 mg, Vitamin E 40 mg, Coenzyme Q10 20 mg and Selenomethionine 83 µg
  • Reduction in the levels of SGPT, SGOT, ALP and γ-GT
66140 mg/day p.o.
  • Decrease in SGPT, SGOT and lipid profile levels
  • Reduction in FBS, serum insulin levels and HOMA index
36540 mg bid. p.o.; 3 monthsVitamin E
  • Decrease in γ-GT and fibrosis scores
30188 mg p.o.; 6 monthsVitamin E and Phospholipids
  • Reduction in fatty liver index levels
17994 mg bid. p.o.; 12 monthsPhosphatidylcholine 194 mg and Vitamin E 89 mg
  • Improvement in SGPT, SGOT, γ-GT, TGF-β and MMP-2 levels
150303 mg bid. p.o.; 6 monthsVitamin D 10 mg and Vitamin E 15 mg
  • Reduction in the levels of HOMA-IR, CH, TG, IL-18, IL-22, CRP, IGF-II, TNF-α, TGF-β, EGFR, MMP-2 and CD-44
  • Improvement in SGPT and γ-GT levels
62303 mg bid. p.o.; 6 monthsVitamin D 10 mg and Vitamin E 15 mg
  • Decrease in levels of TBARS, SGPT, HOMA-IR, TNF-α and CRP
  • Elevation in plasmatic levels of estrogens
NASH64210 mg/day p.o.; 8 weeks
  • Reduction in BMI and the level of SGPT and SGOT
100700 mg tid; 48 weeks
  • Decrease in fibrosis
  • Reduction in levels of SGPT and SGOT
116420 and 700 mg tid, p.o.; 48 weeks
  • Improves fibrosis
Multiple sclerosis therapy-induce liver damage54
(diagnosed with remitting relapsing multiple sclerosis)
420 mg, p.o.; 6 monthsIFNβ
  • Reduction in SGPT, SGOT, L-17 and IFNγ
  • Decrease in Th1 and Th17 cell population and increase in Treg cell population
  • Increase in IL-10 and TGF-β levels
Chronic HCV infection6447 mg p.o; 12 monthsRibavirin+Peg–IFN and Vitamin E+ phospholipids
  • Significant decrease in viral load and reduction in plasma markers of liver fibrosis
265, 10, 15, and 20 mg/kg/day i.v.; 7 and 14 daysRibavirin+
  • Reduction in HCV RNA production
154420 and 700 mg tid p.o.; 24 weeks
  • Reduction in SGPT levels
  • No change in HCV RNA levels
HIV/HCV coinfection1620 mg/kg/day i.v.; 14 daysRibavirin+
Peg–IFN and Telaprevir for 12 weeks
  • Reduction in HCV RNA production
Anti TB drug-induced hepatotoxicity55140 mg tid p.o.; 8 weeksRifampicin 10 mg/kg/day, Isoniazid 5 mg/kg/day, Ethambutol 15 mg/kg/day or Pyrazinamide 25 mg/kg/day
  • Decrease in SGPT, SGOT, γ-GT, ALP and total protein levels
70140 mg tid p.o.; 2 weeksIsoniazid 5 mg/kg, Pyrazinamide 20 mg/kg, Ethambutol 15 mg/kg and/or Rifampin 10 mg/kg
  • No significant hepatoprotective effect
108140 mg bid p.o.; 8 weeksIsoniazid, Pyrazinamide, Ethambutol and/or Rifampin
  • No significant hepatoprotective effect
49140 mg tid p.o.; 9 monthsDesferrioxamine
  • Decrease in serum iron levels and total iron-binding capacity
25420 mg/ day p.o.; 12 weeksDesferrioxamine 40 mg/kg/day
  • Reduction in TNF-α and serum neopterin levels
  • Increase in IFNγ and IL-4 production
40140 mg tid p.o.; 6 monthsDeferasirox
  • Decrease in serum ferritin levels
22420 mg/ day p.o.; 6 monthsDesferrioxamine
  • Decrease in TGF-β, IL-23, IL-17 and IL-10 levels
80420 mg/ day p.o.; 9 monthsDeferiprone
  • Decrease in serum ferritin and iron level
  • No change in blood urea, bilirubin, SGPT, SGOT or creatinine levels
Notably, silymarin has also been reported as a potential candidate for the treatment of alopecia. An in vitro study on human dermal papilla cells conducted by Cheon et al. (2019) demonstrated that therapy with silybin augments the spheroid formation of dermal papilla cells and induces hair-growth properties by triggering AKT and Wnt/β-catenin signaling pathways [283]. Silymarin also plays a crucial role in wound repair and healing. Oryan et al. (2012) reported that silymarin lessens lymphocyte and macrophage cell counts along with elevation in the number of fibrocytes, collagen fibers and fibroblasts [286]. Indeed, regulation of inflammation and oxidation are also essential during wound healing. Studies reported that treatment with silymarin and its active constituents considerably reduces IL-6 and IL-8 discharge and up-regulates IL-8 mRNA expression via NF-κB and AP-1 activation [279]. Furthermore, COX and NOS also help in the progression of wound healing, and silymarin can elevate NOS expression while reducing COX-2 mRNA production [284,285].

3. Conclusions

Findings from this review indicate that silymarin is a multifunctional extract which possesses the competency to modulate various cell signaling pathways and induce diverse therapeutic activities. Silymarin is a whole mixture containing different compounds, including silybins A and B, isosilybins A and B, silychristin and silydianin. Silybin is quantitatively the main component of silymarin. Thus, the literature has mainly focused on this compound while ignoring all other components. This leads to problems in reproducibility of the scientific results. Thus, further studies should individually address the main constituents of this mixture which are responsible for the biological activity and determine potential neutral, synergistic and antagonistic effects between these compounds. The inclusion of purified constituents from the silymarin mixture is needed to clarify the bioactivities of the respective compounds in future studies. Moreover, recent advancements in isolation and identification of phytochemicals have also drawn increased attention to the application of herbal medicines as potential targets for the management of various diseases. Silymarin portrays broad anti-inflammatory, antioxidant and pro-apoptotic properties (Figure 7) and modulates various transcription factors (NFκB, PPAR-γ, Nrf2, β-catenin, AP-1, WT-1, kLF6, IRS-1, SREBP-1c, CREB and GADD45α), growth factors such as BDNF, TGF-β and VEGF, receptors (LDL, estrogen receptor, GLP-1, Farnesyl x and Chemokine 4 and 5), signaling pathways (MAPK/ERK2/p53, Slit-2/Robo, Notch, CDK, Wnt/ β-catenin P13K-PKB/Akt, mTOR, IRS-1/P13K/Akt and Jak-STAT), gene expression of apoptotic proteins (Bax, Bcl-2, Bcl-XL, Bim, Caspase 3, 8, 9, FADD and Survivin) and inflammatory cytokines (IL-1β, 2, 5, 6, 8, 12, TNFα, IFNγ, MIPα and MCP-1) while impairing several enzymes (COX-2, iNOS, SGPT, SGOT, MMP, MPO, AChE, G6Pase, MAO-B, LDH, Telomerase, FAS and CK-MB) and activating endogenous antioxidant enzymes, which are consequently accountable for the numerous biological and pharmacological activities reported for silymarin, including hepatoprotection, neuroprotection, cardioprotection and anti-cancer, anti-viral and anti-diabetic properties as evidenced through numerous studies and experimental data.
Therefore, silymarin may be employed as a potential candidate for managing and treating various diseases as a complementary and alternative medicine.

Author Contributions

K.W.: Writing—Original Draft, Investigation; R.P.: Conceptualization, Validation, Writing—Review and Editing, Supervision; M.K.: Data Curation; S.K.: Data Curation; P.C.S.: Conceptualization, Writing—Review and Editing, Supervision; G.S.: Writing—Review and Editing, Supervision; R.V.: Writing—Review and Editing; V.M.: Writing—Review and Editing; I.S.: Writing—Review and Editing; D.K.: Writing—Review and Editing, Supervision; P.J.: Writing—Review and Editing, Validation, Supervision. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Data Availability Statement

All the associated data are available within the manuscript.

Conflicts of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Sample Availability

Samples of the compounds are available from the authors.

List of Abbreviations

α-SMAα-Smooth muscle actin
γGTGamma-glutamyl transferase
ALPAlkaline phosphate
AP-1Activated protein-1
APPAmyloid precursor protein
Amyloid β
BDNFbrain-derived neurotrophic factors
BidTwo times a day
CDCyclin D
CDCA3Cell division cycle-associated 3 protein
CDKCyclin-dependent kinase
CK1αCasein kinase 1α
CK-MBCreatine kinase-MB
COL-α1Collagen α1
CPDs Cyclobutane pyrimidine dimers
CREBcAMP response element-binding protein
CRPC-reactive protein
DMDiabetes Mellitus
DRP1Dynamin-related protein 1
ERK1/2Extracellular signal-regulated kinase
FADDFas-associated death domain
FASFatty acid synthase
FBSFasting blood sugar
FoxM1Forkhead box M1
GADD45αGrowth arrest and DNA damage-inducible protein α
GM-CSFGranulocyte-macrophage colony stimulating factor
GLP-1Glucagon-like peptide 1
GSK3βGlycogen synthase kinase-3β
HBVHepatitis B virus
HCVHepatitis C virus
HFDHigh-fat diet
HIF 1αHypoxia inducible factor 1α
HIVHuman immunodeficiency virus
HOMA-IRHomeostatic model assessment of insulin resistance
HSCHepatic stellate cells
ICAM-1Intercellular adhesion molecule-1
IFN-γInterferon γ
IKKIkB kinase
iNOSInducible nitric oxide synthase
IRS1Insulin receptor substrate 1
JAKJanus Kinase
JNKc-Jun NH2-terminal kinase
KLF 6Krueppel-like factor 6
LDHLactate dehydrogenase
LRP6Lipoprotein receptor-related protein 6
MAO-BMonoamine oxidase-B
MAPKMitogen-activated protein kinases
MCD dietMethionine–choline deficient diet
MCP-1Monocyte chemoattractant protein-1
MMPMatrix metalloproteinases
mTORMammalian target of rapamycin
NAFLDNon-alcoholic fatty liver disease
NASHNon-alcoholic steatohepatitis
NF-ĸBNuclear factor kappa B
NGFNerve growth factor
NLRP3NLR family pyrin domain containing 3
NONitric oxide
NPRNucleotide excision repair
Nrf2Nuclear factor erythroid 2-related factor 2
NUSAP1Nucleolar and spindle-associated protein 1
PARPPoly adenosine diphosphate-ribose polymerase
PI3KPhosphatidylinositol 3-kinase
PKB/AKtProtein kinase B
ROSReactive oxygen species
SAPKStress-activated protein kinase
SARS-CoV2Severe acute respiratory syndrome coronavirus 2
SGOTSerum glutamic-oxalacetic transaminase
SGPTSerum glutamic-pyruvic transaminase
SODSuperoxide dismutase
SREBP-1cSterol regulatory element-binding protein 1c
STATSignal transducers and activators of transcription
TBARSThiobarbituric acid reactive substances
TGF-βTransforming growth factor β
TidThree times a day
TIMP-1Tissue inhibitor of metalloproteinases 1
TNF-αTumor necrosis factor α
TOPBP1Topoisomerase 2 binding protein 1
TRAILTNF-related apoptosis inducing ligand
TrkBTropomyosin receptor kinase B
VEGFVascular endothelial growth factor


  1. Nikam, P.H.; Kareparamban, J.; Jadhav, A.; Kadam, V. Future Trends in Standardization of Herbal Drugs. J. Appl. Pharm. Sci. 2012, 2, 38–44. [Google Scholar] [CrossRef]
  2. Saller, R.; Melzer, J.; Reichling, J.; Brignoli, R.; Meier, R. An Updated Systematic Review of the Pharmacology of Silymarin. Forsch. Komplement. 2007, 14, 70–80. [Google Scholar] [CrossRef] [PubMed]
  3. Bhattacharya, S. Phytotherapeutic Properties of Milk Thistle Seeds: An Overview. J. Adv. Pharm. Educ. Res. 2011, 1, 69–79. [Google Scholar]
  4. Das, S.K.; Mukherjee, S.; Vasudevan, D.M. Medicinal Properties of Milk Thistle with Special Reference to Silymarin An Overview. Nat. Prod. Radiance 2008, 7, 182–192. [Google Scholar]
  5. Ghosh, A.; Ghosh, T.; Jain, S. Silymarin—A Review on the Pharmacodynamics and Bioavailability Enhancement Approaches. J. Pharm. Sci. Technol. 2010, 2, 348–355. [Google Scholar]
  6. Schuppan, D.; Jia, J.I.D.; Brinkhaus, B.; Hahn, E.G. Herbal Products for Liver Diseases: A Therapeutic Challenge for the New Millennium. Hepatology 1999, 30, 1099–1104. [Google Scholar] [CrossRef] [Green Version]
  7. Ramasamy, K.; Agarwal, R. Multitargeted Therapy of Cancer by Silymarin. Cancer Lett. 2008, 269, 352–362. [Google Scholar] [CrossRef] [Green Version]
  8. Sharma, A.; Puri, V.; Kakkar, V.; Singh, I. Formulation and Evaluation of Silymarin-Loaded Chitosan-Montmorilloite Microbeads for the Potential Treatment of Gastric Ulcers. J. Funct. Biomater. 2018, 9, 52. [Google Scholar] [CrossRef] [Green Version]
  9. Chang, L.W.; Hou, M.L.; Tsai, T.H. Silymarin in Liposomes and Ethosomes: Pharmacokinetics and Tissue Distribution in Free-Moving Rats by High-Performance Liquid Chromatography-Tandem Mass Spectrometry. J. Agric. Food Chem. 2014, 62, 11657–11665. [Google Scholar] [CrossRef]
  10. Flora, K.; Hahn, M.; Rosen, H.; Benner, K. Milk Thistle (Silybum marianum) for the Therapy of Liver Disease. Am. J. Gastroenterol. 1998, 93, 139–143. [Google Scholar] [CrossRef]
  11. Gazak, R.; Walterova, D.; Kren, V. Silybin and Silymarin-New and Emerging Applications in Medicine. Curr. Med. Chem. 2007, 14, 315–338. [Google Scholar] [CrossRef] [PubMed]
  12. Neha; Jaggi, A.; Singh, N. Silymarin and Its Role in Chronic Diseases. In Advances in Experimental Medicine and Biology; Springer: Berlin/Hamburg, Germany, 2016; Volume 929, pp. 25–44. [Google Scholar]
  13. Palit, P.; Mukhopadhyay, A.; Chattopadhyay, D. Phyto-Pharmacological Perspective of Silymarin: A Potential Prophylactic or Therapeutic Agent for COVID-19, Based on Its Promising Immunomodulatory, Anti-Coagulant and Anti-Viral Property. Phyther. Res. 2021, 35, 4246–4257. [Google Scholar] [CrossRef] [PubMed]
  14. Abenavoli, L.; Izzo, A.A.; Milić, N.; Cicala, C.; Santini, A.; Capasso, R. Milk Thistle (Silybum marianum): A Concise Overview on Its Chemistry, Pharmacological, and Nutraceutical Uses in Liver Diseases. Phyther. Res. 2018, 32, 2202–2213. [Google Scholar] [CrossRef]
  15. Lv, Y.; Gao, S.; Xu, S.; Du, G.; Zhou, J.; Chen, J. Spatial Organization of Silybin Biosynthesis in Milk Thistle [Silybum marianum (L.) Gaertn]. Plant J. 2017, 92, 995–1004. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Bijak, M. Silybin, a Major Bioactive Component of Milk Thistle (Silybum marianum L. Gaernt.)—Chemistry, Bioavailability, and Metabolism. Molecules 2017, 22, 1942. [Google Scholar] [CrossRef] [Green Version]
  17. Dixit, N.; Baboota, S.; Kohli, K.; Ahmad, S.; Ali, J. Silymarin: A Review of Pharmacological Aspects and Bioavailability Enhancement Approaches. Indian J. Pharmacol. 2007, 39, 172–179. [Google Scholar] [CrossRef] [Green Version]
  18. Elwekeel, A.; Elfishawy, A.; Abouzid, S. Silymarin Content in Silybum marianum Fruits at Different Maturity Stages. J. Med. Plants Res. 2013, 7, 1665–1669. [Google Scholar] [CrossRef]
  19. Javed, S.; Kohli, K.; Ali, M. Reassessing Bioavailability of Silymarin. Altern. Med. Rev. 2011, 16, 239–249. [Google Scholar]
  20. Reddy, K.R. Silymarin for the treatment of chronic liver disease. Gastroenterol. Hepatol. (N. Y.) 2007, 3, 825–826. [Google Scholar]
  21. Kaur, M.; Agarwal, R. Silymarin and Epithelial Cancer Chemoprevention: How Close We Are to Bedside? Toxicol. Appl. Pharmacol. 2007, 224, 350–359. [Google Scholar] [CrossRef] [Green Version]
  22. Javed, S.; Ahsan, W.; Kohli, K. Pharmacological Influences of Natural Products as Bioenhancers of Silymarin against Carbon Tetrachloride-Induced Hepatotoxicity in Rats. Clin. Phytoscience 2018, 4, 18. [Google Scholar] [CrossRef]
  23. Home-Nano Silymarin OIC NEW: Nano Silymarin OIC NEW. Available online: (accessed on 5 July 2022).
  24. Zhang, Z.; Li, X.; Sang, S.; McClements, D.J.; Chen, L.; Long, J.; Jiao, A.; Wang, J.; Jin, Z.; Qiu, C. A Review of Nanostructured Delivery Systems for the Encapsulation, Protection, and Delivery of Silymarin: An Emerging Nutraceutical. Food. Res. Int. 2022, 156, 111314. [Google Scholar] [CrossRef]
  25. Wadhwa, K.; Kadian, V.; Puri, V.; Bhardwaj, B.Y.; Sharma, A.; Pahwa, R.; Rao, R.; Gupta, M.; Singh, I. New Insights into Quercetin Nanoformulations for Topical Delivery. Phytomedicine Plus 2022, 2, 100257. [Google Scholar] [CrossRef]
  26. Saini, V.; Singh, A.; Shukla, R.; Jain, K.; Yadav, A.K. Silymarin-Encapsulated Xanthan Gum–Stabilized Selenium Nanocarriers for Enhanced Activity against Amyloid Fibril Cytotoxicity. AAPS PharmSciTech 2022, 23, 125. [Google Scholar] [CrossRef]
  27. Elfaky, M.A.; Sirwi, A.; Ismail, S.H.; Awad, H.H.; Gad, S.S. Hepatoprotective Effect of Silver Nanoparticles at Two Different Particle Sizes: Comparative Study with and without Silymarin. Curr. Issues Mol. Biol. 2022, 44, 2923–2938. [Google Scholar] [CrossRef]
  28. Abdullah, A.S.; El Sayed, I.E.T.; El-Torgoman, A.M.A.; Kalam, A.; Wageh, S.; Kamel, M.A. Green Synthesis of Silymarin–Chitosan Nanoparticles as a New Nano Formulation with Enhanced Anti-Fibrotic Effects against Liver Fibrosis. Int. J. Mol. Sci. 2022, 23, 5420. [Google Scholar] [CrossRef]
  29. Patel, P.; Raval, M.; Manvar, A.; Airao, V.; Bhatt, V.; Shah, P. Lung Cancer Targeting Efficiency of Silibinin Loaded Poly Caprolactone/Pluronic F68 Inhalable Nanoparticles: In Vitro and In Vivo Study. PLoS ONE 2022, 17, e0267257. [Google Scholar] [CrossRef]
  30. Iqbal, J.; Andleeb, A.; Ashraf, H.; Meer, B.; Mehmood, A.; Jan, H.; Zaman, G.; Nadeem, M.; Drouet, S.; Fazal, H.; et al. Potential Antimicrobial, Antidiabetic, Catalytic, Antioxidant and ROS/RNS Inhibitory Activities of Silybum marianum Mediated Biosynthesized Copper Oxide Nanoparticles. RSC Adv. 2022, 12, 14069–14083. [Google Scholar] [CrossRef]
  31. Staroverov, S.A.; Kozlov, S.V.; Fomin, A.S.; Gabalov, K.P.; Khanadeev, V.A.; Soldatov, D.A.; Domnitsky, I.Y.; Dykman, L.A.; Akchurin, S.V.; Guliy, O.I. Synthesis of Silymarin−selenium Nanoparticle Conjugate and Examination of Its Biological Activity in Vitro. ADMET DMPK 2021, 9, 255–266. [Google Scholar] [CrossRef]
  32. Silymarin|Side Effects|Dosage|Precautions|Medicine. Available online: (accessed on 5 July 2022).
  33. Han, Y.; Guo, D.; Chen, Y.; Chen, Y.; Tan, Z.R.; Zhou, H.H. Effect of Silymarin on the Pharmacokinetics of Losartan and Its Active Metabolite E-3174 in Healthy Chinese Volunteers. Eur. J. Clin. Pharmacol. 2009, 65, 585–591. [Google Scholar] [CrossRef]
  34. Moltó, J.; Valle, M.; Miranda, C.; Cedeño, S.; Negredo, E.; Clotet, B. Effect of Milk Thistle on the Pharmacokinetics of Darunavir-Ritonavir in HIV-Infected Patients. Antimicrob. Agents Chemother. 2012, 56, 2837–2841. [Google Scholar] [CrossRef] [Green Version]
  35. Almazroo, O.A.; Miah, M.K.; Venkataramanan, R. Drug Metabolism in the Liver. Clin. Liver Dis. 2017, 21, 1–20. [Google Scholar] [CrossRef]
  36. Derosa, G.; Bonaventura, A.; Bianchi, L.; Romano, D.; D’angelo, A.; Fogari, E.; Maffioli, P. Berberis Aristata/Silybum marianum Fixed Combination on Lipid Profile and Insulin Secretion in Dyslipidemic Patients. Expert Opin. Biol. Ther. 2013, 13, 1495–1506. [Google Scholar] [CrossRef]
  37. Derosa, G.; Romano, D.; D’Angelo, A.; Maffioli, P. Berberis Aristata Combined with Silybum marianum on Lipid Profile in Patients Not Tolerating Statins at High Doses. Atherosclerosis 2015, 239, 87–92. [Google Scholar] [CrossRef]
  38. Derosa, G.; D’Angelo, A.; Romano, D.; Maffioli, P. Effects of a Combination of Berberis Aristata, Silybum marianum and Monacolin on Lipid Profile in Subjects at Low Cardiovascular Risk; A Double-Blind, Randomized, Placebo-Controlled Trial. Int. J. Mol. Sci. 2017, 18, 343. [Google Scholar] [CrossRef] [Green Version]
  39. Mengesha, T.; Sekaran, N.G.; Mehare, T. Hepatoprotective Effect of Silymarin on Fructose Induced Nonalcoholic Fatty Liver Disease in Male Albino Wistar Rats. BMC Complement. Med. Ther. 2021, 21, 104. [Google Scholar] [CrossRef]
  40. Abdel-Moneim, A.M.; Al-Kahtani, M.A.; El-Kersh, M.A.; Al-Omair, M.A. Free Radical-Scavenging, Anti-Inflammatory/Anti-Fibrotic and Hepatoprotective Actions of Taurine and Silymarin against CCl4 Induced Rat Liver Damage. PLoS ONE 2015, 10, e0144509. [Google Scholar] [CrossRef] [Green Version]
  41. Tsai, J.H.; Liu, J.Y.; Wu, T.T.; Ho, P.C.; Huang, C.Y.; Shyu, J.C.; Hsieh, Y.S.; Tsai, C.C.; Liu, Y.C. Effects of Silymarin on the Resolution of Liver Fibrosis Induced by Carbon Tetrachloride in Rats. J. Viral Hepat. 2008, 15, 508–514. [Google Scholar] [CrossRef]
  42. Sokar, S.S.; El-Sayad, M.E.S.; Ghoneim, M.E.S.; Shebl, A.M. Combination of Sitagliptin and Silymarin Ameliorates Liver Fibrosis Induced by Carbon Tetrachloride in Rats. Biomed. Pharmacother. 2017, 89, 98–107. [Google Scholar] [CrossRef]
  43. Keshavarz-Maleki, R.; Shalmani, A.A.; Gholami, M.; Sabzevari, S.; Rahimzadegan, M.; Jeivad, F.; Sabzevari, O. The Ameliorative Effect of Monomethyl Fumarate and Silymarin against Valproic Acid Induced Hepatotoxicity in Rats. Pharm. Chem. J. 2021, 55, 240–245. [Google Scholar] [CrossRef]
  44. Chen, I.S.; Chen, Y.C.; Chou, C.H.; Chuang, R.F.; Sheen, L.Y.; Chiu, C.H. Hepatoprotection of Silymarin against Thioacetamide-Induced Chronic Liver Fibrosis. J. Sci. Food Agric. 2012, 92, 1441–1447. [Google Scholar] [CrossRef]
  45. Heidarian, E.; Nouri, A. Hepatoprotective Effects of Silymarin against Diclofenac-Induced Liver Toxicity in Male Rats Based on Biochemical Parameters and Histological Study. Arch. Physiol. Biochem. 2021, 127, 112–118. [Google Scholar] [CrossRef] [PubMed]
  46. Mahli, A.; Koch, A.; Czech, B.; Peterburs, P.; Lechner, A.; Haunschild, J.; Müller, M.; Hellerbrand, C. Hepatoprotective Effect of Oral Application of a Silymarin Extract in Carbon Tetrachloride-Induced Hepatotoxicity in Rats. Clin. Phytoscience 2015, 1, 5. [Google Scholar] [CrossRef] [Green Version]
  47. Shaker, E.; Mahmoud, H.; Mnaa, S. Silymarin, the Antioxidant Component and Silybum marianum Extracts Prevent Liver Damage. Food Chem. Toxicol. 2010, 48, 803–806. [Google Scholar] [CrossRef]
  48. Freitag, A.F.; Cardia, G.F.E.; Da Rocha, B.A.; Aguiar, R.P.; Silva-Comar, F.M.D.S.; Spironello, R.A.; Grespan, R.; Caparroz-Assef, S.M.; Bersani-Amado, C.A.; Cuman, R.K.N. Hepatoprotective Effect of Silymarin (Silybum marianum) on Hepatotoxicity Induced by Acetaminophen in Spontaneously Hypertensive Rats. Evid.-Based Complement. Altern. Med. 2015, 2015, 1–8. [Google Scholar] [CrossRef] [Green Version]
  49. Haddad, P.S.; Haddad, Y.; Vallerand, D.; Brault, A. Antioxidant and Hepatoprotective Effects of Silibinin in a Rat Model of Nonalcoholic Steatohepatitis. Evid.-Based Complement. Altern. Med. 2011, 2011, 1–10. [Google Scholar] [CrossRef] [Green Version]
  50. Zhu, S.Y.; Jiang, N.; Yang, J.; Tu, J.; Zhou, Y.; Xiao, X.; Dong, Y. Silybum marianum Oil Attenuates Hepatic Steatosis and Oxidative Stress in High Fat Diet-Fed Mice. Biomed. Pharmacother. 2018, 100, 191–197. [Google Scholar] [CrossRef]
  51. Ou, Q.; Weng, Y.; Wang, S.; Zhao, Y.; Zhang, F.; Zhou, J.; Wu, X. Silybin Alleviates Hepatic Steatosis and Fibrosis in NASH Mice by Inhibiting Oxidative Stress and Involvement with the NF-κB Pathway. Dig. Dis. Sci. 2018, 63, 3398–3408. [Google Scholar] [CrossRef] [PubMed]
  52. Aghazadeh, S.; Amini, R.; Yazdanparast, R.; Ghaffari, S.H. Anti-Apoptotic and Anti-Inflammatory Effects of Silybum marianum in Treatment of Experimental Steatohepatitis. Exp. Toxicol. Pathol. 2011, 63, 569–574. [Google Scholar] [CrossRef]
  53. Kim, S.H.; Oh, D.S.; Oh, J.Y.; Son, T.G.; Yuk, D.Y.; Jung, Y.S. Silymarin Prevents Restraint Stress-Induced Acute Liver Injury by Ameliorating Oxidative Stress and Reducing Inflammatory Response. Molecules 2016, 21, 443. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Zhang, B.; Xu, D.; She, L.; Wang, Z.; Yang, N.; Sun, R.; Zhang, Y.; Yan, C.; Wei, Q.; Aa, J.; et al. Silybin Inhibits NLRP3 Inflammasome Assembly through the NAD+/SIRT2 Pathway in Mice with Nonalcoholic Fatty Liver Disease. FASEB J. 2018, 32, 757–767. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Alaca, N.; Özbeyli, D.; Uslu, S.; Şahin, H.H.; Yiǧittörk, G.; Kurtel, H.; Öktem, G.; Yeǧen, B.Ç. Treatment with Milk Thistle Extract (Silybum marianum), Ursodeoxycholic Acid, or Their Combination Attenuates Cholestatic Liver Injury in Rats: Role of the Hepatic Stem Cells. Turkish J. Gastroenterol. 2017, 28, 476–484. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Fried, M.W.; Navarro, V.J.; Afdhal, N.; Belle, S.H.; Wahed, A.S.; Hawke, R.L.; Doo, E.; Meyers, C.M.; Reddy, K.R. Effect of Silymarin (Milk Thistle) on Liver Disease in Patients with Chronic Hepatitis C Unsuccessfully Treated with Interferon Therapy: A Randomized Controlled Trial. JAMA-J. Am. Med. Assoc. 2012, 308, 274–282. [Google Scholar] [CrossRef]
  57. Clichici, S.; Olteanu, D.; Nagy, A.L.; Oros, A.; Filip, A.; Mircea, P.A. Silymarin Inhibits the Progression of Fibrosis in the Early Stages of Liver Injury in CCl4-Treated Rats. J. Med. Food 2015, 18, 290–298. [Google Scholar] [CrossRef]
  58. Raghu, R.; Karthikeyan, S. Zidovudine and Isoniazid Induced Liver Toxicity and Oxidative Stress: Evaluation of Mitigating Properties of Silibinin. Environ. Toxicol. Pharmacol. 2016, 46, 217–226. [Google Scholar] [CrossRef] [PubMed]
  59. Malaguarnera, M.; Di Rosa, M.; Nicoletti, F.; Malaguarnera, L. Molecular Mechanisms Involved in NAFLD Progression. J. Mol. Med. 2009, 87, 679–695. [Google Scholar] [CrossRef] [PubMed]
  60. Shaarawy, S.M.; Tohamy, A.A.; Elgendy, S.M.; Abd Elmageed, Z.Y.; Bahnasy, A.; Mohamed, M.S.; Kandil, E.; Matrougui, K. Protective Effects of Garlic and Silymarin on NDEA-Induced Rats Hepatotoxicity. Int. J. Biol. Sci. 2009, 5, 549–557. [Google Scholar] [CrossRef]
  61. Federico, A.; Dallio, M.; Masarone, M.; Gravina, A.G.; Di Sarno, R.; Tuccillo, C.; Cossiga, V.; Lama, S.; Stiuso, P.; Morisco, F.; et al. Evaluation of the Effect Derived from Silybin with Vitamin D and Vitamin E Administration on Clinical, Metabolic, Endothelial Dysfunction, Oxidative Stress Parameters, and Serological Worsening Markers in Nonalcoholic Fatty Liver Disease Patients. Oxid. Med. Cell. Longev. 2019, 2019, 1–12. [Google Scholar] [CrossRef]
  62. Gharagozloo, M.; Jafari, S.; Esmaeil, N.; Javid, E.N.; Bagherpour, B.; Rezaei, A. Immunosuppressive Effect of Silymarin on Mitogen-Activated Protein Kinase Signalling Pathway: The Impact on T Cell Proliferation and Cytokine Production. Basic Clin. Pharmacol. Toxicol. 2013, 113, 209–214. [Google Scholar] [CrossRef]
  63. Sinha, K.; Das, J.; Pal, P.B.; Sil, P.C. Oxidative Stress: The Mitochondria-Dependent and Mitochondria-Independent Pathways of Apoptosis. Arch. Toxicol. 2013, 87, 1157–1180. [Google Scholar] [CrossRef]
  64. Kisseleva, T.; Brenner, D. Molecular and Cellular Mechanisms of Liver Fibrosis and Its Regression. Nat. Rev. Gastroenterol. Hepatol. 2020, 18, 151–166. [Google Scholar] [CrossRef] [PubMed]
  65. Fuchs, E.C.; Weyhenmeyer, R.; Weiner, O.H. Effects of Silibinin and of a Synthetic Analogue on Isolated Rat Hepatic Stellate Cells and Myofibroblasts. Arzneimittelforschung 1997, 47, 1383–1387. [Google Scholar] [PubMed]
  66. Deshmane, S.L.; Kremlev, S.; Amini, S.; Sawaya, B.E. Monocyte Chemoattractant Protein-1 (MCP-1): An Overview. J. Interf. Cytokine Res. 2009, 29, 313–325. [Google Scholar] [CrossRef] [PubMed]
  67. Tsuruta, S.; Nakamuta, M.; Enjoji, M.; Kotoh, K.; Hiasa, K.; Egashira, K.; Nawata, H. Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Prevents Dimethylnitrosamine-Induced Hepatic Fibrosis in Rats. Int. J. Mol. Med. 2004, 14, 837–842. [Google Scholar] [CrossRef] [PubMed]
  68. Hemmann, S.; Graf, J.; Roderfeld, M.; Roeb, E. Expression of MMPs and TIMPs in Liver Fibrosis-a Systematic Review with Special Emphasis on Anti-Fibrotic Strategies. J. Hepatol. 2007, 46, 955–975. [Google Scholar] [CrossRef]
  69. Loguercio, C.; Andreone, P.; Brisc, C.; Brisc, M.C.; Bugianesi, E.; Chiaramonte, M.; Cursaro, C.; Danila, M.; De Sio, I.; Floreani, A.; et al. Silybin Combined with Phosphatidylcholine and Vitamin e in Patients with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial. Free Radic. Biol. Med. 2012, 52, 1658–1665. [Google Scholar] [CrossRef] [Green Version]
  70. Dehmlow, C.; Erhard, J.; De Groot, H. Inhibition of Kupffer Cell Functions as an Explanation for the Hepatoprotective Properties of Silibinin. Hepatology 1996, 23, 749–754. [Google Scholar] [CrossRef]
  71. Sonnenbichler, J.; Goldbero, M.; Hane, L.; Madubunyi, I.; Vogl, S.; Zetl, I. Stimulatory Effect of Silibinin on the DNA Synthesis in Partially Hepatectomized Rat Livers: Non-Response in Hepatoma and Other Malign Cell Lines. Biochem. Pharmacol. 1986, 35, 538–541. [Google Scholar] [CrossRef]
  72. Yormaz, S.; Bulbuloglu, E.; Kurutas, E.B.; Ciralik, H.; Yuzbasioglu, M.F.; Yildiz, H.; Coskuner, I.; Silay, E.; Kantarceken, B.; Goksu, M.; et al. The Comparison of the Effects of Hepatic Regeneration after Partial Hepatectomy, Silybum Marinaum, Propofol, N-Acetylcysteine and Vitamin E on Liver. Bratislava Med. J. 2012, 113, 145–151. [Google Scholar] [CrossRef] [Green Version]
  73. Thakur, V.; Choudhary, M.; Garg, A.; Choudhary, N.; Jangra, A.; Budhwar, V. Evaluation of a Hydroalcoholic Extract of the Leaves from the Endangered Medicinal Plant Gloriosa Superba Linn. (Colchicaceae) for Its Potential Anti-Diabetic Effect. Arch. Med. 2015, 7, 1–8. [Google Scholar]
  74. Sharma, S.; Wadhwa, K.; Choudhary, M.; Budhwar, V. Ethnopharmacological Perspectives of Glucokinase Activators in the Treatment of Diabetes Mellitus. Nat. Prod. Res. 2021, 1–15. [Google Scholar] [CrossRef] [PubMed]
  75. Feng, B.; Meng, R.; Huang, B.; Shen, S.; Bi, Y.; Zhu, D. Silymarin Alleviates Hepatic Oxidative Stress and Protects against Metabolic Disorders in High-Fat Diet-Fed Mice. Free Radic. Res. 2016, 50, 314–327. [Google Scholar] [CrossRef] [PubMed]
  76. Rahimi, R.; Karimi, J.; Khodadadi, I.; Tayebinia, H.; Kheiripour, N.; Hashemnia, M.; Goli, F. Silymarin Ameliorates Expression of Urotensin II (U-II) and Its Receptor (UTR) and Attenuates Toxic Oxidative Stress in the Heart of Rats with Type 2 Diabetes. Biomed. Pharmacother. 2018, 101, 244–250. [Google Scholar] [CrossRef] [PubMed]
  77. Alabdan, M.A. Silymarin Ameliorates Metabolic Risk Factors and Protects against Cardiac Apoptosis in Streptozotocin-Induced Diabetic Rats. Biomed. Biotechnol. 2015, 3, 20–27. [Google Scholar] [CrossRef]
  78. Abu-zaiton, A.S. Evaluating the Effect of Silybum marianum Extract on Blood Glucose, Liver and Kidney Functions in Diabetic Rats. Adv. Stud. Biol. 2013, 5, 447–454. [Google Scholar] [CrossRef]
  79. Gu, M.; Zhao, P.; Huang, J.; Zhao, Y.; Wang, Y.; Li, Y.; Li, Y.; Fan, S.; Ma, Y.M.; Tong, Q.; et al. Silymarin Ameliorates Metabolic Dysfunction Associated with Diet-Induced Obesity via Activation of Farnesyl X Receptor. Front. Pharmacol. 2016, 7, 345. [Google Scholar] [CrossRef] [Green Version]
  80. Talaat Elgarf, A.; Maher Mahdy, M.; Sabri, N.A. Effect of Silymarin Supplementation on Glycemic Control, Lipid Profile and Insulin Resistance in Patients with Type 2 Diabetes Mellitus. Int. J. Adv. Res. 2015, 3, 812–821. [Google Scholar]
  81. Numan, A.T.; Hadi, N.A.; Sh Mohammed, N.; Hussain, S.A. Use of Silymarine as Adjuvant in Type 1 Diabetes Mellitus Patients Poorly Controlled with Insulin. J. Fac. Med. Baghdad 2010, 52, 75–79. [Google Scholar] [CrossRef]
  82. Velussi, M.; Cernigoi, A.M.; Ariella, D.M.; Dapas, F.; Caffau, C.; Zilli, M. Long-Term (12 Months) Treatment with an Anti-Oxidant Drug (Silymarin) Is Effective on Hyperinsulinemia, Exogenous Insulin Need and Malondialdehyde Levels in Cirrhotic Diabetic Patients. J. Hepatol. 1997, 26, 871–879. [Google Scholar] [CrossRef]
  83. Huseini, H.F.; Larijani, B.; Heshmat, R.; Fakhrzadeh, H.; Radjabipour, B.; Toliat, T.; Raza, M. The Efficacy of Silybum marianum (L.) Gaertn. (Silymarin) in the Treatment of Type II Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial. Phyther. Res. 2006, 20, 1036–1039. [Google Scholar] [CrossRef]
  84. Hussain, S.A.R. Silymarin as an Adjunct to Glibenclamide Therapy Improves Long-Term and Postprandial Glycemic Control and Body Mass Index in Type 2 Diabetes. J. Med. Food 2007, 10, 543–547. [Google Scholar] [CrossRef]
  85. Guigas, B.; Naboulsi, R.; Villanueva, G.R.; Taleux, N.; Lopez-Novoa, J.M.; Leverve, X.M.; El-Mir, M.Y. The Flavonoid Silibinin Decreases Glucose-6-Phosphate Hydrolysis in Perifused Rat Hepatocytes by an Inhibitory Effect on Glucose-6-Phosphatase. Cell. Physiol. Biochem. 2007, 20, 925–934. [Google Scholar] [CrossRef] [PubMed]
  86. Feng, B.; Huang, B.; Jing, Y.; Shen, S.; Feng, W.; Wang, W.; Meng, R.; Zhu, D. Silymarin Ameliorates the Disordered Glucose Metabolism of Mice with Diet-Induced Obesity by Activating the Hepatic SIRT1 Pathway. Cell. Signal. 2021, 84, 110023. [Google Scholar] [CrossRef] [PubMed]
  87. Guo, Y.; Wang, S.; Wang, Y.; Zhu, T. Silymarin Improved Diet-Induced Liver Damage and Insulin Resistance by Decreasing Inflammation in Mice. Pharm. Biol. 2016, 54, 2995–3000. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Soto, C.; Raya, L.; Juárez, J.; Pérez, J.; González, I. Effect of Silymarin in Pdx-1 Expression and the Proliferation of Pancreatic β-Cells in a Pancreatectomy Model. Phytomedicine 2014, 21, 233–239. [Google Scholar] [CrossRef]
  89. Qin, N.; Hu, X.; Li, S.; Wang, J.; Li, Z.; Li, D.; Xu, F.; Gao, M.; Hua, H. Hypoglycemic Effect of Silychristin A from Silybum marianum Fruit via Protecting Pancreatic Islet β Cells from Oxidative Damage and Inhibiting α-Glucosidase Activity In Vitro and in Rats with Type 1 Diabetes. J. Funct. Foods 2017, 38, 168–179. [Google Scholar] [CrossRef]
  90. Xu, F.; Yang, J.; Negishi, H.; Sun, Y.; Li, D.; Zhang, X.; Hayashi, T.; Gao, M.; Ikeda, K.; Ikejima, T. Silibinin Decreases Hepatic Glucose Production through the Activation of Gut–Brain–Liver Axis in Diabetic Rats. Food Funct. 2018, 9, 4926–4935. [Google Scholar] [CrossRef]
  91. Amniattalab, A.; Malekinejad, H.; Rezabakhsh, A.; Rokhsartalab-Azar, S.; Alizade-Fanalou, S. Silymarin: A Novel Natural Agent to Restore Defective Pancreatic β Cells in Streptozotocin (STZ)-Induced Diabetic Rats. Iran. J. Pharm. Res. 2016, 15, 493–500. [Google Scholar] [CrossRef]
  92. Malekinejad, H.; Rezabakhsh, A.; Rahmani, F.; Hobbenaghi, R. Silymarin Regulates the Cytochrome P450 3A2 and Glutathione Peroxides in the Liver of Streptozotocin-Induced Diabetic Rats. Phytomedicine 2012, 19, 583–590. [Google Scholar] [CrossRef]
  93. Kim, E.J.; Kim, J.; Lee, M.Y.; Sudhanva, M.S.; Devakumar, S.; Jeon, Y.J. Silymarin Inhibits Cytokine-Stimulated Pancreatic Beta Cells by Blocking the ERK1/2 Pathway. Biomol. Ther. 2014, 22, 282–287. [Google Scholar] [CrossRef] [Green Version]
  94. Soto, C.; Raya, L.; Pérez, J.; González, I.; Pérez, S. Silymarin Induces Expression of Pancreatic Nkx6.1 Transcription Factor and β-Cells Neogenesis in a Pancreatectomy Model. Molecules 2014, 19, 4654–4668. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Li, H.B.; Yang, Y.R.Y.; Mo, Z.J.; Ding, Y.; Jiang, W.J. Silibinin Improves Palmitate-Induced Insulin Resistance in C2C12 Myotubes by Attenuating IRS-1/PI3K/AKt Pathway Inhibition. Braz. J. Med. Biol. Res. 2015, 48, 440–446. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Yang, J.; Sun, Y.; Xu, F.; Liu, W.; Hayashi, T.; Onodera, S.; Tashiro, S.I.; Ikejima, T. Involvement of Estrogen Receptors in Silibinin Protection of Pancreatic β-Cells from TNFα- or IL-1β-Induced Cytotoxicity. Biomed. Pharmacother. 2018, 102, 344–353. [Google Scholar] [CrossRef] [PubMed]
  97. Sun, Y.; Yang, J.; Liu, W.; Yao, G.; Xu, F.; Hayashi, T.; Onodera, S.; Ikejima, T. Attenuating Effect of Silibinin on Palmitic Acid-Induced Apoptosis and Mitochondrial Dysfunction in Pancreatic β-Cells Is Mediated by Estrogen Receptor Alpha. Mol. Cell. Biochem. 2019, 460, 81–92. [Google Scholar] [CrossRef]
  98. Wang, J.; Zhang, X.; Zhang, L.; Yan, T.; Wu, B.; Xu, F.; Jia, Y. Silychristin A Activates Nrf2-HO-1/SOD2 Pathway to Reduce Apoptosis and Improve GLP-1 Production through Upregulation of Estrogen Receptor α in GLUTag Cells. Eur. J. Pharmacol. 2020, 881, 173236. [Google Scholar] [CrossRef]
  99. Stolf, A.M.; Cardoso, C.C.; Acco, A. Effects of Silymarin on Diabetes Mellitus Complications: A Review. Phyther. Res. 2017, 31, 366–374. [Google Scholar] [CrossRef]
  100. Tuorkey, M.J.; El-Desouki, N.I.; Kamel, R.A. Cytoprotective Effect of Silymarin against Diabetes-Induced Cardiomyocyte Apoptosis in Diabetic Rats. Biomed. Environ. Sci. 2015, 28, 36–43. [Google Scholar] [CrossRef]
  101. Meng, S.; Yang, F.; Wang, Y.; Qin, Y.; Xian, H.; Che, H.; Wang, L. Silymarin Ameliorates Diabetic Cardiomyopathy via Inhibiting TGF-Β1/Smad Signaling. Cell Biol. Int. 2019, 43, 65–72. [Google Scholar] [CrossRef] [Green Version]
  102. Sheela, N.; Jose, M.A.; Sathyamurthy, D.; Kumar, B.N. Effect of Silymarin on Streptozotocin-Nicotinamide-Induced Type 2 Diabetic Nephropathy in Rats. Iran. J. Kidney Dis. 2013, 7, 117–123. [Google Scholar]
  103. Vessal, G.; Akmali, M.; Najafi, P.; Moein, M.R.; Sagheb, M.M. Silymarin and Milk Thistle Extract May Prevent the Progression of Diabetic Nephropathy in Streptozotocin-Induced Diabetic Rats. Ren. Fail. 2010, 32, 733–739. [Google Scholar] [CrossRef] [Green Version]
  104. Guzel, S.; Sahinogullari, Z.U.; Canacankatan, N.; Antmen, S.E.; Kibar, D.; Coskun Yilmaz, B. Potential Renoprotective Effects of Silymarin against Vancomycin-Induced Nephrotoxicity in Rats. Drug Chem. Toxicol. 2020, 43, 630–636. [Google Scholar] [CrossRef]
  105. Chen, Y.; Chen, L.; Yang, T. Silymarin Nanoliposomes Attenuate Renal Injury on Diabetic Nephropathy Rats via Co-Suppressing TGF-β/Smad and JAK2/STAT3/SOCS1 Pathway. Life Sci. 2021, 271, 119197. [Google Scholar] [CrossRef]
  106. Fallahzadeh, M.K.; Dormanesh, B.; Sagheb, M.M.; Roozbeh, J.; Vessal, G.; Pakfetrat, M.; Daneshbod, Y.; Kamali-Sarvestani, E.; Lankarani, K.B. Effect of Addition of Silymarin to Renin-Angiotensin System Inhibitors on Proteinuria in Type 2 Diabetic Patients with Overt Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial. Am. J. Kidney Dis. 2012, 60, 896–903. [Google Scholar] [CrossRef] [Green Version]
  107. Zhang, H.T.; Shi, K.; Baskota, A.; Zhou, F.L.; Chen, Y.X.; Tian, H.M. Silybin Reduces Obliterated Retinal Capillaries in Experimental Diabetic Retinopathy in Rats. Eur. J. Pharmacol. 2014, 740, 233–239. [Google Scholar] [CrossRef]
  108. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
  109. Mattiuzzi, C.; Lippi, G. Current Cancer Epidemiology. J. Epidemiol. Glob. Health 2019, 9, 217–222. [Google Scholar] [CrossRef] [Green Version]
  110. Elsayed, E.A.; Sharaf-Eldin, M.A.; Wadaan, M. In Vitro Evaluation of Cytotoxic Activities of Essential Oil from Moringa oleifera Seeds on HeLa, HepG2, MCF-7, CACO-2 and L929 Cell Lines. Asian Pacific J. Cancer Prev. 2015, 16, 4671–4675. [Google Scholar] [CrossRef] [Green Version]
  111. Liang, C.; Pan, H.; Li, H.; Zhao, Y.; Feng, Y. In Vitro Anticancer Activity and Cytotoxicity Screening of Phytochemical Extracts from Selected Traditional Chinese Medicinal Plants. J. Balk. Union Oncol. 2017, 22, 543–551. [Google Scholar]
  112. Wang, X.; Zhang, Z.; Wu, S.C. Health Benefits of Silybum marianum: Phytochemistry, Pharmacology, and Applications. J. Agric. Food Chem. 2020, 68, 11644–11664. [Google Scholar] [CrossRef]
  113. Hosseinabadi, T.; Lorigooini, Z.; Tabarzad, M.; Salehi, B.; Rodrigues, C.F.; Martins, N.; Sharifi-Rad, J. Silymarin Antiproliferative and Apoptotic Effects: Insights into Its Clinical Impact in Various Types of Cancer. Phyther. Res. 2019, 33, 2849–2861. [Google Scholar] [CrossRef]
  114. Elyasi, S.; Shojaee, F.S.R.; Allahyari, A.; Karimi, G. Topical Silymarin Administration for Prevention of Capecitabine-Induced Hand–Foot Syndrome: A Randomized, Double-Blinded, Placebo-Controlled Clinical Tria. Phyther. Res. 2017, 31, 1323–1329. [Google Scholar] [CrossRef]
  115. Shahbazi, F.; Sadighi, S.; Dashti-Khavidaki, S.; Shahi, F.; Mirzania, M.; Abdollahi, A.; Ghahremani, M.H. Effect of Silymarin Administration on Cisplatin Nephrotoxicity: Report from a Pilot, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Phyther. Res. 2015, 29, 1046–1053. [Google Scholar] [CrossRef]
  116. Momeni, A.; Hajigholami, A.; Geshnizjani, S.; Kheiri, S. Effect of Silymarin in the Prevention of Cisplatin Nephrotoxicity, a Clinical Trial Study. J. Clin. Diagn. Res. 2015, 9, 11–13. [Google Scholar] [CrossRef]
  117. Elyasi, S.; Hosseini, S.; Niazi Moghadam, M.R.; Aledavood, S.A.; Karimi, G. Effect of Oral Silymarin Administration on Prevention of Radiotherapy Induced Mucositis: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Phyther. Res. 2016, 30, 1879–1885. [Google Scholar] [CrossRef]
  118. Karbasforooshan, H.; Hosseini, S.; Elyasi, S.; Fani Pakdel, A.; Karimi, G. Topical Silymarin Administration for Prevention of Acute Radiodermatitis in Breast Cancer Patients: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Phyther. Res. 2019, 33, 379–386. [Google Scholar] [CrossRef]
  119. Becker-Schiebe, M.; Mengs, U.; Schaefer, M.; Bulitta, M.; Hoffmann, W. Topical Use of a Silymarin-Based Preparation to Prevent Radiodermatitis: Results of a Prospective Study in Breast Cancer Patients. Strahlenther. Onkol. 2011, 187, 485–491. [Google Scholar] [CrossRef]
  120. Imai-Sumida, M.; Chiyomaru, T.; Majid, S.; Saini, S.; Nip, H.; Dahiya, R.; Tanaka, Y.; Yamamura, S. Silibinin Suppresses Bladder Cancer through Down-Regulation of Actin Cytoskeleton and PI3K/Akt Signaling Pathways. Oncotarget 2017, 8, 92032–92042. [Google Scholar] [CrossRef] [Green Version]
  121. Kim, S.H.; Choo, G.-S.; Yoo, E.S.; Woo, J.S.; Lee, J.H.; Han, S.H.; Jung, S.H.; Kim, H.J.; Jung, J.Y. Silymarin Inhibits Proliferation of Human Breast Cancer Cells via Regulation of the MAPK Signaling Pathway and Induction of Apoptosis. Oncol. Lett. 2021, 21, 492. [Google Scholar] [CrossRef]
  122. Permana, M.Y.; Soediro, T.M.; Louisa, M. Silymarin Increases the Sensitivity of Breast Cancer Cells to Doxorubicin in Doxorubicin-Induced MCF-7 Cells by Inhibiting Breast Cancer Resistance Protein Expression. J. Phys. Conf. Ser. 2018, 1073, 032055. [Google Scholar] [CrossRef] [Green Version]
  123. Forghani, P.; Khorramizadeh, M.R.; Waller, E.K. Silibinin Inhibits Accumulation of Myeloid-Derived Suppressor Cells and Tumor Growth of Murine Breast Cancer. Cancer Med. 2014, 3, 215–224. [Google Scholar] [CrossRef]
  124. Si, L.; Fu, J.; Liu, W.; Hayashi, T.; Nie, Y.; Mizuno, K.; Hattori, S.; Fujisaki, H.; Onodera, S.; Ikejima, T. Silibinin Inhibits Migration and Invasion of Breast Cancer MDA-MB-231 Cells through Induction of Mitochondrial Fusion. Mol. Cell. Biochem. 2020, 463, 189–201. [Google Scholar] [CrossRef] [PubMed]
  125. Dastpeyman, M.; Motamed, N.; Azadmanesh, K.; Mostafavi, E.; Kia, V.; Jahanian-Najafabadi, A.; Shokrgozar, M.A. Inhibition of Silibinin on Migration and Adhesion Capacity of Human Highly Metastatic Breast Cancer Cell Line, MDA-MB-231, by Evaluation of Β1-Integrin and Downstream Molecules, Cdc42, Raf-1 and D4GDI. Med. Oncol. 2012, 29, 2512–2518. [Google Scholar] [CrossRef] [PubMed]
  126. Byun, H.J.; Darvin, P.; Kang, D.Y.; Sp, N.; Joung, Y.H.; Park, J.H.; Kim, S.J.; Yang, Y.M. Silibinin Downregulates MMP2 Expression via Jak2/STAT3 Pathway and Inhibits the Migration and Invasive Potential in MDA-MB-231 Cells. Oncol. Rep. 2017, 37, 3270–3278. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Lee, S.O.; Jeong, Y.J.; Im, H.G.; Kim, C.H.; Chang, Y.C.; Lee, I.S. Silibinin Suppresses PMA-Induced MMP-9 Expression by Blocking the AP-1 Activation via MAPK Signaling Pathways in MCF-7 Human Breast Carcinoma Cells. Biochem. Biophys. Res. Commun. 2007, 354, 165–171. [Google Scholar] [CrossRef]
  128. Kim, S.; Choi, J.H.; Lim, H.I.; Lee, S.K.; Kim, W.W.; Kim, J.S.; Kim, J.H.; Choe, J.H.; Yang, J.H.; Nam, S.J.; et al. Silibinin Prevents TPA-Induced MMP-9 Expression and VEGF Secretion by Inactivation of the Raf/MEK/ERK Pathway in MCF-7 Human Breast Cancer Cells. Phytomedicine 2009, 16, 573–580. [Google Scholar] [CrossRef]
  129. Lu, W.; Lin, C.; King, T.D.; Chen, H.; Reynolds, R.C.; Li, Y. Silibinin Inhibits Wnt/β-Catenin Signaling by Suppressing Wnt Co-Receptor LRP6 Expression in Human Prostate and Breast Cancer Cells. Cell. Signal. 2012, 24, 2291–2296. [Google Scholar] [CrossRef] [Green Version]
  130. Kauntz, H.; Bousserouel, S.; Gosse, F.; Marescaux, J.; Raul, F. Silibinin, a Natural Flavonoid, Modulates the Early Expression of Chemoprevention Biomarkers in a Preclinical Model of Colon Carcinogenesis. Int. J. Oncol. 2012, 41, 849–854. [Google Scholar] [CrossRef] [Green Version]
  131. Kauntz, H.; Bousserouel, S.; Gossé, F.; Raul, F. Silibinin Triggers Apoptotic Signaling Pathways and Autophagic Survival Response in Human Colon Adenocarcinoma Cells and Their Derived Metastatic Cells. Apoptosis 2011, 16, 1042–1053. [Google Scholar] [CrossRef]
  132. Eo, H.J.; Park, G.H.; Song, H.M.; Lee, J.W.; Kim, M.K.; Lee, M.H.; Lee, J.R.; Koo, J.S.; Jeong, J.B. Silymarin Induces Cyclin D1 Proteasomal Degradation via Its Phosphorylation of Threonine-286 in Human Colorectal Cancer Cells. Int. Immunopharmacol. 2015, 24, 1–6. [Google Scholar] [CrossRef]
  133. Eo, H.J.; Jeong, J.B.; Koo, J.S.; Jeong, H.J. Silymarin-Mediated Degradation of c-Myc Contributes to the Inhibition of Cell Proliferation in Human Colorectal Cancer Cells. Korean J. Plant Resour. 2017, 30, 265–271. [Google Scholar] [CrossRef]
  134. Wang, J.Y.; Chang, C.C.; Chiang, C.C.; Chen, W.M.; Hung, S.C. Silibinin Suppresses the Maintenance of Colorectal Cancer Stem-like Cells by Inhibiting PP2A/AKT/MTOR Pathways. J. Cell. Biochem. 2012, 113, 1733–1743. [Google Scholar] [CrossRef]
  135. Kim, S.H.; Choo, G.S.; Yoo, E.S.; Woo, J.S.; Han, S.H.; Lee, J.H.; Jung, J.Y. Silymarin Induces Inhibition of Growth and Apoptosis through Modulation of the MAPK Signaling Pathway in AGS Human Gastric Cancer Cells. Oncol. Rep. 2019, 42, 1904–1914. [Google Scholar] [CrossRef] [Green Version]
  136. Li, R.; Yu, J.; Wang, C. Silibinin Promotes the Apoptosis of Gastric Cancer BGC823 Cells through Caspase Pathway. J. BUON 2017, 22, 1148–1153. [Google Scholar] [PubMed]
  137. Wang, Y.X.; Cai, H.; Jiang, G.; Zhou, T.B.; Wu, H. Silibinin Inhibits Proliferation, Induces Apoptosis and Causes Cell Cycle Arrest in Human Gastric Cancer MGC803 Cells via STAT3 Pathway Inhibition. Asian Pacific J. Cancer Prev. 2014, 15, 6791–6798. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  138. Zappavigna, S.; Vanacore, D.; Lama, S.; Potenza, N.; Russo, A.; Ferranti, P.; Dallio, M.; Federico, A.; Loguercio, C.; Sperlongano, P.; et al. Silybin-Induced Apoptosis Occurs in Parallel to the Increase of Ceramides Synthesis and Mirnas Secretion in Human Hepatocarcinoma Cells. Int. J. Mol. Sci. 2019, 20, 2190. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Gu, H.R.; Park, S.C.; Choi, S.; Lee, J.C.; Kim, Y.C.; Han, C.J.; Kim, J.; Yang, K.Y.; Kim, Y.J.; Noh, G.Y.; et al. Combined Treatment with Silibinin and Either Sorafenib or Gefitinib Enhances Their Growth-Inhibiting Effects in Hepatocellular Carcinoma Cells. Clin. Mol. Hepatol. 2015, 21, 49–59. [Google Scholar] [CrossRef]
  140. Bektur Aykanat, N.E.; Kacar, S.; Karakaya, S.; Sahinturk, V. Silymarin Suppresses HepG2 Hepatocarcinoma Cell Progression through Downregulation of Slit-2/Robo-1 Pathway. Pharmacol. Rep. 2020, 72, 199–207. [Google Scholar] [CrossRef]
  141. Zhang, S.; Yang, Y.; Liang, Z.; Duan, W.; Yang, J.; Yan, J.; Wang, N.; Feng, W.; Ding, M.; Nie, Y.; et al. Silybin-Mediated Inhibition of Notch Signaling Exerts Antitumor Activity in Human Hepatocellular Carcinoma Cells. PLoS ONE 2013, 8, 83699. [Google Scholar] [CrossRef] [Green Version]
  142. Ramakrishnan, G.; Jagan, S.; Kamaraj, S.; Anandakumar, P.; Devaki, T. Silymarin Attenuated Mast Cell Recruitment Thereby Decreased the Expressions of Matrix Metalloproteinases-2 and 9 in Rat Liver Carcinogenesis. Invest. New Drugs 2009, 27, 233–240. [Google Scholar] [CrossRef]
  143. Yang, X.; Li, X.; An, L.; Bai, B.; Chen, J. Silibinin Induced the Apoptosis of Hep-2 Cells via Oxidative Stress and down-Regulating Survivin Expression. Eur. Arch. Oto-Rhino-Laryngol. 2013, 270, 2289–2297. [Google Scholar] [CrossRef]
  144. Faezizadeh, Z.; Mesbah-Namin, S.A.R.; Allameh, A. The Effect of Silymarin on Telomerase Activity in the Human Leukemia Cell Line K562. Planta Med. 2012, 78, 899–902. [Google Scholar] [CrossRef] [PubMed]
  145. Guo, S.; Bai, X.; Liu, Y.; Shi, S.; Wang, X.; Zhan, Y.; Kang, X.; Chen, Y.; An, H. Inhibition of TMEM16A by Natural Product Silibinin: Potential Lead Compounds for Treatment of Lung Adenocarcinoma. Front. Pharmacol. 2021, 12, 736. [Google Scholar] [CrossRef] [PubMed]
  146. Won, D.H.; Kim, L.H.; Jang, B.; Yang, I.H.; Kwon, H.J.; Jin, B.; Oh, S.H.; Kang, J.H.; Hong, S.D.; Shin, J.A.; et al. In Vitro and In Vivo Anti-Cancer Activity of Silymarin on Oral Cancer. Tumor Biol. 2018, 40, 1010428318776170. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Choi, E.S.; Oh, S.; Jang, B.; Yu, H.J.; Shin, J.A.; Cho, N.P.; Yang, I.H.; Won, D.H.; Kwon, H.J.; Hong, S.D.; et al. Silymarin and Its Active Component Silibinin Act as Novel Therapeutic Alternatives for Salivary Gland Cancer by Targeting the ERK1/2-Bim Signaling Cascade. Cell. Oncol. 2017, 40, 235–246. [Google Scholar] [CrossRef] [PubMed]
  148. Iyengar, R.M.; Devaraj, E. Silibinin Triggers the Mitochondrial Pathway of Apoptosis in Human Oral Squamous Carcinoma Cells. Asian Pacific J. Cancer Prev. 2020, 21, 1877–1882. [Google Scholar] [CrossRef]
  149. Fan, L.; Ma, Y.; Liu, Y.; Zheng, D.; Huang, G. Silymarin Induces Cell Cycle Arrest and Apoptosis in Ovarian Cancer Cells. Eur. J. Pharmacol. 2014, 743, 79–88. [Google Scholar] [CrossRef]
  150. Kacar, S.; Bektur Aykanat, N.E.; Sahinturk, V. Silymarin Inhibited DU145 Cells by Activating SLIT2 Protein and Suppressing Expression of CXCR4. Med. Oncol. 2020, 37, 18. [Google Scholar] [CrossRef]
  151. Singh, R.P.; Tyagi, A.K.; Zhao, J.; Agarwal, R. Silymarin Inhibits Growth and Causes Regression of Established Skin Tumors in SENCAR Mice via Modulation of Mitogen-Activated Protein Kinases and Induction of Apoptosis. Carcinogenesis 2002, 23, 499–510. [Google Scholar] [CrossRef] [Green Version]
  152. Vaid, M.; Prasad, R.; Sun, Q.; Katiyar, S.K. Silymarin Targets B-Catenin Signaling in Blocking Migration/Invasion of Human Melanoma Cells. PLoS ONE 2011, 6, e23000. [Google Scholar] [CrossRef]
  153. Khan, A.Q.; Khan, R.; Tahir, M.; Rehman, M.U.; Lateef, A.; Ali, F.; Hamiza, O.O.; Hasan, S.K.; Sultana, S. Silibinin Inhibits Tumor Promotional Triggers and Tumorigenesis against Chemically Induced Two-Stage Skin Carcinogenesis in Swiss Albino Mice: Possible Role of Oxidative Stress and Inflammation. Nutr. Cancer 2014, 66, 249–258. [Google Scholar] [CrossRef]
  154. Vaid, M.; Singh, T.; Prasad, R.; Katiyar, S.K. Silymarin Inhibits Melanoma Cell Growth Both In Vitro and In Vivo by Targeting Cell Cycle Regulators, Angiogenic Biomarkers and Induction of Apoptosis. Mol. Carcinog. 2015, 54, 1328–1339. [Google Scholar] [CrossRef] [PubMed]
  155. Kalla, P.K.; Chitti, S.; Aghamirzaei, S.T.; Senthilkumar, R.; Arjunan, S. Anti-Cancer Activity of Silymarin on MCF-7 and NCIH-23 Cell Lines. Adv. Biol. Res. 2014, 8, 57–61. [Google Scholar] [CrossRef]
  156. Vinh, P.Q.; Sugie, S.; Tanaka, T.; Hara, A.; Yamada, Y.; Katayama, M.; Deguchi, T.; Mori, H. Chemopreventive Effects of a Flavonoid Antioxidant Silymarin on N-Butyl-N-(4-Hydroxybutyl)Nitrosamine-Induced Urinary Bladder Carcinogenesis in Male ICR Mice. Jpn. J. Cancer Res. 2002, 93, 42–49. [Google Scholar] [CrossRef] [PubMed]
  157. Feng, N.; Luo, J.; Guo, X. Silybin Suppresses Cell Proliferation and Induces Apoptosis of Multiple Myeloma Cells via the PI3K/Akt/MTOR Signaling Pathway. Mol. Med. Rep. 2016, 13, 3243–3248. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  158. Huang, Q.; Wu, L.J.; Tashiro, S.I.; Onodera, S.; Li, L.H.; Ikejima, T. Silymarin Augments Human Cervical Cancer HeLa Cell Apoptosis via P38/JNK MAPK Pathways in Serum-Free Medium. J. Asian Nat. Prod. Res. 2005, 7, 701–709. [Google Scholar] [CrossRef]
  159. Deep, G.; Oberlies, N.H.; Kroll, D.J.; Agarwal, R. Identifying the Differential Effects of Silymarin Constituents on Cell Growth and Cell Cycle Regulatory Molecules in Human Prostate Cancer Cells. Int. J. Cancer 2008, 123, 41–50. [Google Scholar] [CrossRef]
  160. Bhatia, N.; Agarwal, R. Detrimental Effect of Cancer Preventive Phytochemicals Silymarin, Genistein and Epigallocatechin 3-Gallate on Epigenetic Events in Human Prostate Carcinoma DU145 Cells. Prostate 2001, 46, 98–107. [Google Scholar] [CrossRef]
  161. Katiyar, S.K.; Roy, A.M.; Baliga, M.S. Silymarin Induces Apoptosis Primarily through a P53-Dependent Pathway Involving Bcl-2/Bax, Cytochrome c Release, and Caspase Activation. Mol. Cancer Ther. 2005, 4, 207–216. [Google Scholar] [CrossRef]
  162. Zi, X.; Agarwal, R. Modulation of Mitogen-Activated Protein Kinase Activation and Cell Cycle Regulators by the Potent Skin Cancer Preventive Agent Silymarin. Biochem. Biophys. Res. Commun. 1999, 263, 528–536. [Google Scholar] [CrossRef]
  163. Vaid, M.; Katiyar, S.K. Molecular Mechanisms of Inhibition of Photocarcinogenesis by Silymarin, a Phytochemical from Milk Thistle (Silybum marianum L. Gaertn.) (Review). Int. J. Oncol. 2010, 36, 1053–1060. [Google Scholar] [CrossRef] [Green Version]
  164. Zhu, Z.; Sun, G. Silymarin Mitigates Lung Impairments in a Rat Model of Acute Respiratory Distress Syndrome. Inflammopharmacology 2018, 26, 747–754. [Google Scholar] [CrossRef] [PubMed]
  165. Ramakrishnan, G.; Lo Muzio, L.; Elinos-Báez, C.M.; Jagan, S.; Augustine, T.A.; Kamaraj, S.; Anandakumar, P.; Devaki, T. Silymarin Inhibited Proliferation and Induced Apoptosis in Hepatic Cancer Cells. Cell Prolif. 2009, 42, 229–240. [Google Scholar] [CrossRef] [PubMed]
  166. Aayadi, H.; Mittal, S.P.K.; Deshpande, A.; Gore, M.; Ghaskadbi, S.S. Protective Effect of Geraniin against Carbon Tetrachloride Induced Acute Hepatotoxicity in Swiss Albino Mice. Biochem. Biophys. Res. Commun. 2017, 487, 62–67. [Google Scholar] [CrossRef]
  167. Kim, E.K.; Choi, E.J. Pathological Roles of MAPK Signaling Pathways in Human Diseases. Biochim. Biophys. Acta-Mol. Basis Dis. 2010, 1802, 396–405. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  168. Kauntz, H.; Bousserouel, S.; Gossé, F.; Raul, F. The Flavonolignan Silibinin Potentiates TRAIL-Induced Apoptosis in Human Colon Adenocarcinoma and in Derived TRAIL-Resistant Metastatic Cells. Apoptosis 2012, 17, 797–809. [Google Scholar] [CrossRef]
  169. Zhang, M.; Liu, Y.; Gao, Y.; Li, S. Silibinin-Induced Glioma Cell Apoptosis by PI3K-Mediated but Akt-Independent Downregulation of FoxM1 Expression. Eur. J. Pharmacol. 2015, 765, 346–354. [Google Scholar] [CrossRef]
  170. Shapiro, G.I. Cyclin-Dependent Kinase Pathways as Targets for Cancer Treatment. J. Clin. Oncol. 2006, 24, 1770–1783. [Google Scholar] [CrossRef]
  171. Vijayaraghavan, S.; Moulder, S.; Keyomarsi, K.; Layman, R.M. Inhibiting CDK in Cancer Therapy: Current Evidence and Future Directions. Target. Oncol. 2018, 13, 21–38. [Google Scholar] [CrossRef]
  172. Cui, H.; Li, T.L.; Guo, H.F.; Wang, J.L.; Xue, P.; Zhang, Y.; Fan, J.H.; Li, Z.P.; Gao, Y.J. Silymarin-Mediated Regulation of the Cell Cycle and DNA Damage Response Exerts Antitumor Activity in Human Hepatocellular Carcinoma. Oncol. Lett. 2018, 15, 885–892. [Google Scholar] [CrossRef]
  173. Jung, Y.S.; Park, J. Il Wnt Signaling in Cancer: Therapeutic Targeting of Wnt Signaling beyond β-Catenin and the Destruction Complex. Exp. Mol. Med. 2020, 52, 183–191. [Google Scholar] [CrossRef] [Green Version]
  174. Zhang, Y.; Wang, X. Targeting the Wnt/β-Catenin Signaling Pathway in Cancer. J. Hematol. Oncol. 2020, 13, 165. [Google Scholar] [CrossRef] [PubMed]
  175. Zhou, L.; Wang, D.S.; Li, Q.J.; Sun, W.; Zhang, Y.; Dou, K.F. The Down-Regulation of Notch1 Inhibits the Invasion and Migration of Hepatocellular Carcinoma Cells by Inactivating the Cyclooxygenase-2/Snail/E- Cadherin Pathway In Vitro. Dig. Dis. Sci. 2013, 58, 1016–1025. [Google Scholar] [CrossRef] [PubMed]
  176. de los Fayos Alons Alonso, I.; Liang, H.C.; Turner, S.D.; Lagger, S.; Merkel, O.; Kenner, L. The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas. Cancers 2018, 10, 93. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  177. Chatterjee, S.; Behnam Azad, B.; Nimmagadda, S. The Intricate Role of CXCR4 in Cancer. In Advances in Cancer Research; Academic Press: Cambridge, MA, USA, 2014; Volume 124, pp. 31–82. [Google Scholar]
  178. Bosch-Barrera, J.; Queralt, B.; Menendez, J.A. Targeting STAT3 with Silibinin to Improve Cancer Therapeutics. Cancer Treat. Rev. 2017, 58, 61–69. [Google Scholar] [CrossRef] [PubMed]
  179. Kittur, S.; Wilasrusmee, S.; Pedersen, W.A.; Mattson, M.P.; Straube-West, K.; Wilasrusmee, C.; Jubelt, B.; Kittur, D.S. Neurotrophic and Neuroprotective Effects of Milk Thistle (Silybum marianum) on Neurons in Culture. J. Mol. Neurosci. 2002, 18, 265–269. [Google Scholar] [CrossRef]
  180. Darvesh, A.S.; Carroll, R.T.; Bishayee, A.; Geldenhuys, W.J.; Van Der Schyf, C.J. Oxidative Stress and Alzheimer’s Disease: Dietary Polyphenols as Potential Therapeutic Agents. Expert Rev. Neurother. 2010, 10, 729–745. [Google Scholar] [CrossRef]
  181. Song, X.; Zhou, B.; Cui, L.; Lei, D.; Zhang, P.; Yao, G.; Xia, M.; Hayashi, T.; Hattori, S.; Ushiki-Kaku, Y.; et al. Silibinin Ameliorates Aβ25-35-Induced Memory Deficits in Rats by Modulating Autophagy and Attenuating Neuroinflammation as Well as Oxidative Stress. Neurochem. Res. 2017, 42, 1073–1083. [Google Scholar] [CrossRef]
  182. Al-Enazi, M.M. Neuroprotective Effect of Silymarin by Modulation of Endogenous Biomarkers in Streptozotocin Induced Painful Diabetic Neuropathy. Br. J. Pharmacol. Toxicol. 2013, 4, 110–120. [Google Scholar] [CrossRef]
  183. Song, X.; Zhou, B.; Zhang, P.; Lei, D.; Wang, Y.; Yao, G.; Hayashi, T.; Xia, M.; Tashiro, S.I.; Onodera, S.; et al. Protective Effect of Silibinin on Learning and Memory Impairment in LPS-Treated Rats via ROS–BDNF–TrkB Pathway. Neurochem. Res. 2016, 41, 1662–1672. [Google Scholar] [CrossRef]
  184. Thakare, V.N.; Aswar, M.K.; Kulkarni, Y.P.; Patil, R.R.; Patel, B.M. Silymarin Ameliorates Experimentally Induced Depressive like Behavior in Rats: Involvement of Hippocampal BDNF Signaling, Inflammatory Cytokines and Oxidative Stress Response. Physiol. Behav. 2017, 179, 401–410. [Google Scholar] [CrossRef]
  185. Haddadi, R.; Nayebi, A.M.; Farajniya, S.; Brooshghalan, S.E.; Sharifi, H. Silymarin Improved 6-OHDA-Induced Motor Impairment in Hemi-Parkisonian Rats: Behavioral and Molecular Study. DARU J. Pharm. Sci. 2014, 22, 38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Galhardi, F.; Mesquita, K.; Monserrat, J.M.; Barros, D.M. Effect of Silymarin on Biochemical Parameters of Oxidative Stress in Aged and Young Rat Brain. Food Chem. Toxicol. 2009, 47, 2655–2660. [Google Scholar] [CrossRef] [PubMed]
  187. Nencini, C.; Giorgi, G.; Micheli, L. Protective Effect of Silymarin on Oxidative Stress in Rat Brain. Phytomedicine 2007, 14, 129–135. [Google Scholar] [CrossRef] [PubMed]
  188. Lu, C.W.; Lin, T.Y.; Chiu, K.M.; Lee, M.Y.; Huang, J.H.; Wang, S.J. Silymarin Inhibits Glutamate Release and Prevents against Kainic Acid-Induced Excitotoxic Injury in Rats. Biomedicines 2020, 8, 486. [Google Scholar] [CrossRef]
  189. Ullah, H.; Khan, H. Anti-Parkinson Potential of Silymarin: Mechanistic Insight and Therapeutic Standing. Front. Pharmacol. 2018, 9, 422. [Google Scholar] [CrossRef] [Green Version]
  190. Thome, A.D.; Harms, A.S.; Volpicelli-Daley, L.A.; Standaert, D.G. MicroRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease. J. Neurosci. 2016, 36, 2383–2390. [Google Scholar] [CrossRef]
  191. Pérez-H, J.; Carrillo-S, C.; García, E.; Ruiz-Mar, G.; Pérez-Tamayo, R.; Chavarría, A. Neuroprotective Effect of Silymarin in a MPTP Mouse Model of Parkinson’s Disease. Toxicology 2014, 319, 38–43. [Google Scholar] [CrossRef]
  192. Baluchnejadmojarad, T.; Roghani, M.; Mafakheri, M. Neuroprotective Effect of Silymarin in 6-Hydroxydopamine Hemi-Parkinsonian Rat: Involvement of Estrogen Receptors and Oxidative Stress. Neurosci. Lett. 2010, 480, 206–210. [Google Scholar] [CrossRef]
  193. Srivastava, S.; Sammi, S.R.; Laxman, T.S.; Pant, A.; Nagar, A.; Trivedi, S.; Bhatta, R.S.; Tandon, S.; Pandey, R. Silymarin Promotes Longevity and Alleviates Parkinson’s Associated Pathologies in Caenorhabditis Elegans. J. Funct. Foods 2017, 31, 32–43. [Google Scholar] [CrossRef]
  194. Mazzio, E.A.; Harris, N.; Soliman, K.F.A. Food Constituents Attenuate Monoamine Oxidase Activity and Peroxide Levels in C6 Astrocyte Cells. Planta Med. 1998, 64, 603–606. [Google Scholar] [CrossRef]
  195. de Oliveira, D.R.; Schaffer, L.F.; Busanello, A.; Barbosa, C.P.; Peroza, L.R.; de Freitas, C.M.; Krum, B.N.; Bressan, G.N.; Boligon, A.A.; Athayde, M.L.; et al. Silymarin Has Antioxidant Potential and Changes the Activity of Na+/K+-ATPase and Monoamine Oxidase In Vitro. Ind. Crops Prod. 2015, 70, 347–355. [Google Scholar] [CrossRef]
  196. Wang, M.J.; Lin, W.W.; Chen, H.L.; Chang, Y.H.; Ou, H.C.; Kuo, J.S.; Hong, J.S.; Jeng, K.C.G. Silymarin Protects Dopaminergic Neurons against Lipopolysaccharide-Induced Neurotoxicity by Inhibiting Microglia Activation. Eur. J. Neurosci. 2002, 16, 2103–2112. [Google Scholar] [CrossRef] [PubMed]
  197. Tripathi, M.K.; Rasheed, M.S.U.; Mishra, A.K.; Patel, D.K.; Singh, M.P. Silymarin Protects against Impaired Autophagy Associated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism. J. Mol. Neurosci. 2020, 70, 276–283. [Google Scholar] [CrossRef] [PubMed]
  198. Aboelwafa, H.R.; El-Kott, A.F.; Abd-Ella, E.M.; Yousef, H.N. The Possible Neuroprotective Effect of Silymarin against Aluminum Chloride-Prompted Alzheimer’s-like Disease in Rats. Brain Sci. 2020, 10, 628. [Google Scholar] [CrossRef]
  199. El-Marasy, S.A.A.; Abd-Elsalam, R.M.; Ahmed-Farid, O.A. Ameliorative Effect of Silymarin on Scopolamine-Induced Dementia in Rats. Open Access Maced. J. Med. Sci. 2018, 6, 1215–1224. [Google Scholar] [CrossRef] [Green Version]
  200. Duan, S.; Guan, X.; Lin, R.; Liu, X.; Yan, Y.; Lin, R.; Zhang, T.; Chen, X.; Huang, J.; Sun, X.; et al. Silibinin Inhibits Acetylcholinesterase Activity and Amyloid β Peptide Aggregation: A Dual-Target Drug for the Treatment of Alzheimer’s Disease. Neurobiol. Aging 2015, 36, 1792–1807. [Google Scholar] [CrossRef]
  201. Yaghmaei, P.; Azarfar, K.; Dezfulian, M.; Ebrahim-Habibi, A. Silymarin Effect on Amyloid-β Plaque Accumulation and Gene Expression of APP in an Alzheimer’s Disease Rat Model. DARU J. Pharm. Sci. 2014, 22, 24. [Google Scholar] [CrossRef] [Green Version]
  202. Urata, N.M.; Urakami, K.M.; Zawa, Y.O.; Inoshita, N.K.; Rie, K.I.; Shirasawa, T.; Shimizu, T. Silymarin Attenuated the Amyloid β Plaque Burden and Improved Behavioral Abnormalities in an Alzheimer’s Disease Mouse Model. Biosci. Biotechnol. Biochem. 2010, 74, 2299–2306. [Google Scholar] [CrossRef] [Green Version]
  203. Zheng, H.; Koo, E.H. Biology and Pathophysiology of the Amyloid Precursor Protein. Mol. Neurodegener. 2011, 6, 27. [Google Scholar] [CrossRef] [Green Version]
  204. Lu, P.; Mamiya, T.; Lu, L.L.; Mouri, A.; Zou, L.B.; Nagai, T.; Hiramatsu, M.; Ikejima, T.; Nabeshima, T. Silibinin Prevents Amyloid b Peptide-Induced Memory Impairment and Oxidative Stress in Mice. Br. J. Pharmacol. 2009, 157, 1270–1277. [Google Scholar] [CrossRef] [Green Version]
  205. Zhou, J.; Chao, G.; Li, Y.L.; Wu, M.; Zhong, S.Z.; Feng, Z.Y. Activation of NRF2/ARE by Isosilybin Alleviates Aβ25-35-Induced Oxidative Stress Injury in HT-22 Cells. Neurosci. Lett. 2016, 632, 92–97. [Google Scholar] [CrossRef] [PubMed]
  206. Song, X.; Liu, B.; Cui, L.; Zhou, B.; Liu, L.; Liu, W.; Yao, G.; Xia, M.; Hayashi, T.; Hattori, S.; et al. Estrogen Receptors Are Involved in the Neuroprotective Effect of Silibinin in Aβ1–42-Treated Rats. Neurochem. Res. 2018, 43, 796–805. [Google Scholar] [CrossRef] [PubMed]
  207. Yang, J.; Sun, Y.; Xu, F.; Liu, W.; Hayashi, T.; Hattori, S.; Ushiki-Kaku, Y.; Onodera, S.; Tashiro, S.I.; Ikejima, T. Silibinin Protects Rat Pancreatic β-Cell through up-Regulation of Estrogen Receptors’ Signaling against Amylin- or Aβ1–42-Induced Reactive Oxygen Species/Reactive Nitrogen Species Generation. Phyther. Res. 2019, 33, 998–1009. [Google Scholar] [CrossRef] [PubMed]
  208. Yardım, A.; Kucukler, S.; Özdemir, S.; Çomaklı, S.; Caglayan, C.; Kandemir, F.M.; Çelik, H. Silymarin Alleviates Docetaxel-Induced Central and Peripheral Neurotoxicity by Reducing Oxidative Stress, Inflammation and Apoptosis in Rats. Gene 2021, 769, 145239. [Google Scholar] [CrossRef]
  209. Chtourou, Y.; Fetoui, H.; Sefi, M.; Trabelsi, K.; Barkallah, M.; Boudawara, T.; Kallel, H.; Zeghal, N. Silymarin, a Natural Antioxidant, Protects Cerebral Cortex against Manganese-Induced Neurotoxicity in Adult Rats. BioMetals 2010, 23, 985–996. [Google Scholar] [CrossRef]
  210. Elsawy, H.; Alzahrani, A.M.; Alfwuaires, M.; Sedky, A.; El-Trass, E.E.; Mahmoud, O.; Abdel-Moneim, A.M.; Khalil, M. Analysis of Silymarin-Modulating Effects against Acrylamide-Induced Cerebellar Damage in Male Rats: Biochemical and Pathological Markers. J. Chem. Neuroanat. 2021, 115, 101964. [Google Scholar] [CrossRef]
  211. Hirayama, K.; Oshima, H.; Yamashita, A.; Sakatani, K.; Yoshino, A.; Katayama, Y. Neuroprotective Effects of Silymarin on Ischemia-Induced Delayed Neuronal Cell Death in Rat Hippocampus. Brain Res. 2016, 1646, 297–303. [Google Scholar] [CrossRef]
  212. Wang, C.; Wang, Z.; Zhang, X.; Zhang, X.; Dong, L.; Xing, Y.; Li, Y.; Liu, Z.; Chen, L.; Qiao, H.; et al. Protection by Silibinin against Experimental Ischemic Stroke: Up-Regulated PAkt, PmTOR, HIF-1α and Bcl-2, down-Regulated Bax, NF-κB Expression. Neurosci. Lett. 2012, 529, 45–50. [Google Scholar] [CrossRef]
  213. Khoshnoodi, M.; Fakhraei, N.; Dehpour, A.R. Possible Involvement of Nitric Oxide in Antidepressant-like Effect of Silymarin in Male Mice. Pharm. Biol. 2015, 53, 739–745. [Google Scholar] [CrossRef] [Green Version]
  214. Li, Y.J.; Li, Y.J.; Yang, L.D.; Zhang, K.; Zheng, K.Y.; Wei, X.M.; Yang, Q.; Niu, W.M.; Zhao, M.G.; Wu, Y.M. Silibinin Exerts Antidepressant Effects by Improving Neurogenesis through BDNF/TrkB Pathway. Behav. Brain Res. 2018, 348, 184–191. [Google Scholar] [CrossRef]
  215. Song, X.; Liu, B.; Cui, L.; Zhou, B.; Liu, W.; Xu, F.; Hayashi, T.; Hattori, S.; Ushiki-Kaku, Y.; Tashiro, S.-I.; et al. Silibinin Ameliorates Anxiety/Depression-like Behaviors in Amyloid β-Treated Rats by Upregulating BDNF/TrkB Pathway and Attenuating Autophagy in Hippocampus. Physiol. Behav. 2017, 179, 487–493. [Google Scholar] [CrossRef] [PubMed]
  216. Babu, H.; Ramirez-Rodriguez, G.; Fabel, K.; Bischofberger, J.; Kempermann, G. Synaptic Network Activity Induces Neuronal Differentiation of Adult Hippocampal Precursor Cells through BDNF Signaling. Front. Neurosci. 2009, 1, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  217. Park, H.; Poo, M.M. Neurotrophin Regulation of Neural Circuit Development and Function. Nat. Rev. Neurosci. 2013, 14, 7–23. [Google Scholar] [CrossRef] [PubMed]
  218. Raza, S.S.; Khan, M.M.; Ashafaq, M.; Ahmad, A.; Khuwaja, G.; Khan, A.; Siddiqui, M.S.; Safhi, M.M.; Islam, F. Silymarin Protects Neurons from Oxidative Stress Associated Damages in Focal Cerebral Ischemia: A Behavioral, Biochemical and Immunohistological Study in Wistar Rats. J. Neurol. Sci. 2011, 309, 45–54. [Google Scholar] [CrossRef]
  219. Wang, M.; Li, Y.J.; Ding, Y.; Zhang, H.N.; Sun, T.; Zhang, K.; Yang, L.; Guo, Y.Y.; Liu, S.B.; Zhao, M.G.; et al. Silibinin Prevents Autophagic Cell Death upon Oxidative Stress in Cortical Neurons and Cerebral Ischemia-Reperfusion Injury. Mol. Neurobiol. 2016, 53, 932–943. [Google Scholar] [CrossRef]
  220. Al-Rasheed, N.M.; Al-Rasheed, N.M.; Faddah, L.M.; Mohamed, A.M.; Mohammad, R.A.; Al-Amin, M. Potential Impact of Silymarin in Combination with Chlorogenic Acid and/or Melatonin in Combating Cardiomyopathy Induced by Carbon Tetrachloride. Saudi J. Biol. Sci. 2014, 21, 265–274. [Google Scholar] [CrossRef] [Green Version]
  221. Rao, P.R.; Viswanath, R.K. Cardioprotective Activity of Silymarin in Ischemia-Reperfusion-Induced Myocardial Infarction in Albino Rats. Exp. Clin. Cardiol. 2007, 12, 179–187. [Google Scholar]
  222. Taghiabadi, E.; Imenshahidi, M.; Abnous, K.; Mosafa, F.; Sankian, M.; Memar, B.; Karimi, G. Protective Effect of Silymarin against Acrolein-Induced Cardiotoxicity in Mice. Evid.-Based Complement. Altern. Med. 2012, 2012, 1–14. [Google Scholar] [CrossRef]
  223. Gabrielová, E.; Zholobenko, A.V.; Bartošíková, L.; Nečas, J.; Modriansky, M. Silymarin Constituent 2,3-Dehydrosilybin Triggers Reserpine-Sensitive Positive Inotropic Effect in Perfused Rat Heart. PLoS ONE 2015, 10, e0139208. [Google Scholar] [CrossRef] [Green Version]
  224. Jadhav, G.B.; Upasani, C.D. Antihypertensive Effect of Silymarin on DOCA Salt Induced Hypertension in Unilateral Nephrectomized Rats. Orient. Pharm. Exp. Med. 2011, 11, 101–106. [Google Scholar] [CrossRef]
  225. Jadhav, G.B.; Upasani, C.D. Antihypertensive Effect of Silymarin on Fructose Induced Hypertensive Rats. Indian J. Pharm. Educ. Res. 2012, 46, 26. [Google Scholar]
  226. Ahmed-Belkacem, A.; Ahnou, N.; Barbotte, L.; Wychowski, C.; Pallier, C.; Brillet, R.; Pohl, R.T.; Pawlotsky, J.M. Silibinin and Related Compounds Are Direct Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase. Gastroenterology 2010, 138, 1112–1122. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  227. Wagoner, J.; Negash, A.; Kane, O.J.; Martinez, L.E.; Nahmias, Y.; Bourne, N.; Owen, D.M.; Grove, J.; Brimacombe, C.; McKeating, J.A.; et al. Multiple Effects of Silymarin on the Hepatitis C Virus Lifecycle. Hepatology 2010, 51, 1912–1921. [Google Scholar] [CrossRef] [Green Version]
  228. Anthony, K.; Subramanya, G.; Uprichard, S.; Hammouda, F.; Saleh, M. Antioxidant and Anti-Hepatitis C Viral Activities of Commercial Milk Thistle Food Supplements. Antioxidants 2013, 2, 23–36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  229. Ferenci, P.; Scherzer, T.M.; Kerschner, H.; Rutter, K.; Beinhardt, S.; Hofer, H.; Schöniger-Hekele, M.; Holzmann, H.; Steindl-Munda, P. Silibinin Is a Potent Antiviral Agent in Patients with Chronic Hepatitis C Not Responding to Pegylated Interferon/Ribavirin Therapy. Gastroenterology 2008, 135, 1561–1567. [Google Scholar] [CrossRef] [PubMed]
  230. Sabir, S.; Arshad, M.; Asif, S.; Chaudhari, S.K. An Insight into Medicinal and Therapeutic Potential of Silybum marianum (L.) Gaertn. Int. J. Biosci. 2014, 4, 104–115. [Google Scholar] [CrossRef]
  231. Saller, R.; Meier, R.; Brignoli, R. The Use of Silymarin in the Treatment of Liver Diseases. Drugs 2001, 61, 2035–2063. [Google Scholar] [CrossRef]
  232. Polyak, S.J.; Morishima, C.; Shuhart, M.C.; Wang, C.C.; Liu, Y.; Lee, D.Y.W. Inhibition of T-Cell Inflammatory Cytokines, Hepatocyte NF-κB Signaling, and HCV Infection by Standardized Silymarin. Gastroenterology 2007, 132, 1925–1936. [Google Scholar] [CrossRef]
  233. DebRoy, S.; Hiraga, N.; Imamura, M.; Hayes, C.N.; Akamatsu, S.; Canini, L.; Perelson, A.S.; Pohl, R.T.; Persiani, S.; Uprichard, S.L.; et al. Hepatitis C Virus Dynamics and Cellular Gene Expression in UPA-SCID Chimeric Mice with Humanized Livers during Intravenous Silibinin Monotherapy. J. Viral Hepat. 2016, 23, 708–717. [Google Scholar] [CrossRef] [Green Version]
  234. Blaising, J.; Lévy, P.L.; Gondeau, C.; Phelip, C.; Varbanov, M.; Teissier, E.; Ruggiero, F.; Polyak, S.J.; Oberlies, N.H.; Ivanovic, T.; et al. Silibinin Inhibits Hepatitis C Virus Entry into Hepatocytes by Hindering Clathrin-Dependent Trafficking. Cell. Microbiol. 2013, 15, 1866–1882. [Google Scholar] [CrossRef]
  235. Malaguarnera, G.; Bertino, G.; Chisari, G.; Motta, M.; Vecchio, M.; Vacante, M.; Caraci, F.; Greco, C.; Drago, F.; Nunnari, G.; et al. Silybin Supplementation during HCV Therapy with Pegylated Interferon-α plus Ribavirin Reduces Depression and Anxiety and Increases Work Ability. BMC Psychiatry 2016, 16, 398. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  236. Malaguarnera, M.; Motta, M.; Vacante, M.; Malaguarnera, G.; Caraci, F.; Nunnari, G.; Gagliano, C.; Greco, C.; Chisari, G.; Drago, F.; et al. Silybin-Vitamin E-Phospholipids Complex Reduces Liver Fibrosis in Patients with Chronic Hepatitis C Treated with Pegylated Interferon α and Ribavirin. Am. J. Transl. Res. 2015, 7, 2510–2518. [Google Scholar]
  237. Biermer, M.; Berg, T. Rapid Suppression of Hepatitis C Viremia Induced by Intravenous Silibinin plus Ribavirin. Gastroenterology 2009, 137, 390–391. [Google Scholar] [CrossRef] [PubMed]
  238. Mariño, Z.; Crespo, G.; D’Amato, M.; Brambilla, N.; Giacovelli, G.; Rovati, L.; Costa, J.; Navasa, M.; Forns, X. Intravenous Silibinin Monotherapy Shows Significant Antiviral Activity in HCV-Infected Patients in the Peri-Transplantation Period. J. Hepatol. 2013, 58, 415–420. [Google Scholar] [CrossRef] [PubMed]
  239. Bárcena, R.; Moreno, A.; Rodríguez-Gandía, M.A.; Albillos, A.; Arocena, C.; Blesa, C.; García-Hoz, F.; Graus, J.; Nuño, J.; López-Hervás, P.; et al. Safety and Anti-HCV Effect of Prolonged Intravenous Silibinin in HCV Genotype 1 Subjects in the Immediate Liver Transplant Period. J. Hepatol. 2013, 58, 421–426. [Google Scholar] [CrossRef]
  240. Umetsu, T.; Inoue, J.; Kogure, T.; Kakazu, E.; Ninomiya, M.; Iwata, T.; Takai, S.; Nakamura, T.; Sano, A.; Shimosegawa, T. Inhibitory Effect of Silibinin on Hepatitis B Virus Entry. Biochem. Biophys. Rep. 2018, 14, 20–25. [Google Scholar] [CrossRef] [PubMed]
  241. Speciale, A.; Muscarà, C.; Molonia, M.S.; Cimino, F.; Saija, A.; Giofrè, S.V. Silibinin as Potential Tool against SARS-CoV-2: In Silico Spike Receptor-Binding Domain and Main Protease Molecular Docking Analysis, and In Vitro Endothelial Protective Effects. Phyther. Res. 2021, 35, 4616–4625. [Google Scholar] [CrossRef]
  242. Song, J.H.; Choi, H.J. Silymarin Efficacy against Influenza A Virus Replication. Phytomedicine 2011, 18, 832–835. [Google Scholar] [CrossRef]
  243. Dai, J.P.; Wu, L.Q.; Li, R.; Zhao, X.F.; Wan, Q.Y.; Chen, X.X.; Li, W.Z.; Wang, G.F.; Li, K.S. Identification of 23-(S)-2-Amino-3-Phenylpropanoyl-Silybin as an Antiviral Agent for Influenza A Virus Infection In Vitro and In Vivo. Antimicrob. Agents Chemother. 2013, 57, 4433–4443. [Google Scholar] [CrossRef] [Green Version]
  244. Qaddir, I.; Rasool, N.; Hussain, W.; Mahmood, S. Computer-Aided Analysis of Phytochemicals as Potential Dengue Virus Inhibitors Based on Molecular Docking, ADMET and DFT Studies. J. Vector Borne Dis. 2017, 54, 255–262. [Google Scholar] [CrossRef]
  245. Low, Z.X.; OuYong, B.M.; Hassandarvish, P.; Poh, C.L.; Ramanathan, B. Antiviral Activity of Silymarin and Baicalein against Dengue Virus. Sci. Rep. 2021, 11, 21221. [Google Scholar] [CrossRef] [PubMed]
  246. Camini, F.C.; da Silva, T.F.; da Silva Caetano, C.C.; Almeida, L.T.; Ferraz, A.C.; Alves Vitoreti, V.M.; de Mello Silva, B.; de Queiroz Silva, S.; de Magalhães, J.C.; de Brito Magalhães, C.L. Antiviral Activity of Silymarin against Mayaro Virus and Protective Effect in Virus-Induced Oxidative Stress. Antivir. Res. 2018, 158, 8–12. [Google Scholar] [CrossRef] [PubMed]
  247. Ferraz, A.C.; Almeida, L.T.; da Silva Caetano, C.C.; da Silva Menegatto, M.B.; Souza Lima, R.L.; de Senna, J.P.N.; de Oliveira Cardoso, J.M.; Perucci, L.O.; Talvani, A.; Geraldo de Lima, W.; et al. Hepatoprotective, Antioxidant, Anti-Inflammatory, and Antiviral Activities of Silymarin against Mayaro Virus Infection. Antivir. Res. 2021, 194, 105168. [Google Scholar] [CrossRef] [PubMed]
  248. Lalani, S.S.; Anasir, M.I.; Poh, C.L. Antiviral Activity of Silymarin in Comparison with Baicalein against EV-A71. BMC Complement. Med. Ther. 2020, 20, 97. [Google Scholar] [CrossRef] [Green Version]
  249. Lani, R.; Hassandarvish, P.; Chiam, C.W.; Moghaddam, E.; Chu, J.J.H.; Rausalu, K.; Merits, A.; Higgs, S.; Vanlandingham, D.; Abu Bakar, S.; et al. Antiviral Activity of Silymarin against Chikungunya Virus. Sci. Rep. 2015, 5, 11421. [Google Scholar] [CrossRef] [Green Version]
  250. Lani, R.; Agharbaoui, F.E.; Hassandarvish, P.; Teoh, B.T.; Sam, S.S.; Zandi, K.; Rahman, N.A.; Abubakar, S. In Silico Studies of Fisetin and Silymarin as Novel Chikungunya Virus Nonstructural Proteins Inhibitors. Future Virol. 2021, 16, 167–180. [Google Scholar] [CrossRef]
  251. Cardile, A.P.; Mbuy, G.K.N. Anti-Herpes Virus Activity of Silibinin, the Primary Active Component of Silybum marianum. J. Herb. Med. 2013, 3, 132–136. [Google Scholar] [CrossRef]
  252. McClure, J.; Lovelace, E.S.; Elahi, S.; Maurice, N.J.; Wagoner, J.; Dragavon, J.; Mittler, J.E.; Kraft, Z.; Stamatatos, L.; Horton, H.; et al. Silibinin Inhibits HIV-1 Infection by Reducing Cellular Activation and Proliferation. PLoS ONE 2012, 7, 41832. [Google Scholar] [CrossRef]
  253. McClure, J.; Margineantu, D.H.; Sweet, I.R.; Polyak, S.J. Inhibition of HIV by Legalon-SIL Is Independent of Its Effect on Cellular Metabolism. Virology 2014, 449, 96–103. [Google Scholar] [CrossRef] [Green Version]
  254. Zhou, B.; Wu, L.J.; Li, N.H.; Tashiro, S.I.; Onodera, S.; Uchiumi, F.; Ikejima, T. Silibinin Protects against Isoproterenol-Induced Rat Cardiac Myocyte Injury through Mitochondrial Pathway after up-Regulation of SIRT1. J. Pharmacol. Sci. 2006, 102, 387–395. [Google Scholar] [CrossRef] [Green Version]
  255. Rašković, A.; Stilinović, N.; Kolarović, J.; Vasović, V.; Vukmirović, S.; Mikov, M. The Protective Effects of Silymarin against Doxorubicin-Induced Cardiotoxicity and Hepatotoxicity in Rats. Molecules 2011, 16, 8601–8613. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  256. Esser-Nobis, K.; Romero-Brey, I.; Ganten, T.M.; Gouttenoire, J.; Harak, C.; Klein, R.; Schemmer, P.; Binder, M.; Schnitzler, P.; Moradpour, D.; et al. Analysis of Hepatitis C Virus Resistance to Silibinin In Vitro and In Vivo Points to a Novel Mechanism Involving Nonstructural Protein 4B. Hepatology 2013, 57, 953–963. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  257. Sardanelli, A.M.; Isgrò, C.; Palese, L.L. SARS-CoV-2 Main Protease Active Site Ligands in the Human Metabolome. Molecules 2021, 26, 1409. [Google Scholar] [CrossRef] [PubMed]
  258. Payer, B.A.; Reiberger, T.; Rutter, K.; Beinhardt, S.; Staettermayer, A.F.; Peck-Radosavljevic, M.; Ferenci, P. Successful HCV Eradication and Inhibition of HIV Replication by Intravenous Silibinin in an HIV-HCV Coinfected Patient. J. Clin. Virol. 2010, 49, 131–133. [Google Scholar] [CrossRef] [PubMed]
  259. Braun, D.; Rauch, A.; Durisch, N.; Eberhard, N.; Anagnostopoulos, A.; Ledergerber, B.; Metzner, K.; Böni, J.; Weber, R.; Fehr, J. Efficacy of Lead-in Silibinin and Subsequent Triple Therapy in Difficult-to-Treat HIV/Hepatitis C Virus-Coinfected Patients. HIV Med. 2014, 15, 625–630. [Google Scholar] [CrossRef] [Green Version]
  260. Braun, D.L.; Rauch, A.; Aouri, M.; Durisch, N.; Eberhard, N.; Anagnostopoulos, A.; Ledergerber, B.; Möllhaupt, B.; Metzner, K.J.; Decosterd, L.; et al. A Lead-in with Silibinin Prior to Triple-Therapy Translates into Favorable Treatment Outcomes in Difficult-to-Treat HIV/Hepatitis C Coinfected Patients. PLoS ONE 2015, 10, e0133028. [Google Scholar] [CrossRef] [Green Version]
  261. Bosch-Barrera, J.; Martin-Castillo, B.; Buxó, M.; Brunet, J.; Encinar, J.A.; Menendez, J.A. Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients. J. Clin. Med. 2020, 9, 1770. [Google Scholar] [CrossRef]
  262. Gorla, U.S.; Rao, K.; Kulandaivelu, U.S.; Alavala, R.R.; Panda, S.P. Lead Finding from Selected Flavonoids with Antiviral (SARS-CoV-2) Potentials against COVID-19: An In-Silico Evaluation. Comb. Chem. High Throughput Screen. 2020, 24, 879–890. [Google Scholar] [CrossRef]
  263. Boer, M.; Duchnik, E.; Maleszka, R.; Marchlewicz, M. Structural and Biophysical Characteristics of Human Skin in Maintaining Proper Epidermal Barrier Function. Postep. Dermatol. Alergol. 2016, 33, 1–5. [Google Scholar] [CrossRef]
  264. Benson, H.A.E.; Grice, J.E.; Mohammed, Y.; Namjoshi, S.; Roberts, M.S. Topical and Transdermal Drug Delivery: From Simple Potions to Smart Technologies. Curr. Drug Deliv. 2019, 16, 444–460. [Google Scholar] [CrossRef]
  265. Svobodová, A.; Vostálová, J. Solar Radiation Induced Skin Damage: Review of Protective and Preventive Options. Int. J. Radiat. Biol. 2010, 86, 999–1030. [Google Scholar] [CrossRef] [PubMed]
  266. Guillermo-Lagae, R.; Deep, G.; Ting, H.; Agarwal, C.; Agarwal, R. Silibinin Enhances the Repair of Ultraviolet B-Induced DNA Damage by Activating P53-Dependent Nucleotide Excision Repair Mechanism in Human Dermal Fibroblasts. Oncotarget 2015, 6, 39594–39606. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  267. Katiyar, S.K.; Mantena, S.K.; Meeran, S.M. Silymarin Protects Epidermal Keratinocytes from Ultraviolet Radiation-Induced Apoptosis and DNA Damage by Nucleotide Excision Repair Mechanism. PLoS ONE 2011, 6, e21410. [Google Scholar] [CrossRef] [PubMed]
  268. Roy, S.; Deep, G.; Agarwal, C.; Agarwal, R. Silibinin Prevents Ultraviolet B Radiation-Induced Epidermal Damages in JB6 Cells and Mouse Skin in a P53-GADD45α-Dependent Manner. Carcinogenesis 2012, 33, 629–636. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  269. Rigby, C.M.; Roy, S.; Deep, G.; Guillermo-Lagae, R.; Jain, A.K.; Dhar, D.; Orlicky, D.J.; Agarwal, C.; Agarwal, R. Role of P53 in Silibinin-Mediated Inhibition of Ultraviolet B Radiation-Induced DNA Damage, Inflammation and Skin Carcinogenesis. Carcinogenesis 2017, 38, 40–50. [Google Scholar] [CrossRef] [PubMed]
  270. Carrier, F.; Georgel, P.T.; Pourquier, P.; Blake, M.; Kontny, H.U.; Antinore, M.J.; Gariboldi, M.; Myers, T.G.; Weinstein, J.N.; Pommier, Y.; et al. Gadd45, a P53-Responsive Stress Protein, Modifies DNA Accessibility on Damaged Chromatin. Mol. Cell. Biol. 1999, 19, 1673–1685. [Google Scholar] [CrossRef] [Green Version]
  271. Yang, X.; Zhu, L.; Zhao, W.; He, C.; Li, S.; Xu, C. GADD45α Regulates Cell Proliferation and DNA Repair of BRL-3A Cells That Treated by FZD/UVC via P38, JNK, CDC2/CCNB1, AKT and MTOR Pathways. bioRxiv 2017, 148759. [Google Scholar] [CrossRef] [Green Version]
  272. Gu, M.; Dhanalakshmi, S.; Mohan, S.; Singh, R.P.; Agarwal, R. Silibinin Inhibits Ultraviolet B Radiation-Induced Mitogenic and Survival Signaling, and Associated Biological Responses in SKH-1 Mouse Skin. Carcinogenesis 2005, 26, 1404–1413. [Google Scholar] [CrossRef]
  273. Rajnochová Svobodová, A.; Gabrielová, E.; Ulrichová, J.; Zálešák, B.; Biedermann, D.; Vostálová, J. A Pilot Study of the UVA-Photoprotective Potential of Dehydrosilybin, Isosilybin, Silychristin, and Silydianin on Human Dermal Fibroblasts. Arch. Dermatol. Res. 2019, 311, 477–490. [Google Scholar] [CrossRef]
  274. Rajnochová Svobodová, A.; Gabrielová, E.; Michaelides, L.; Kosina, P.; Ryšavá, A.; Ulrichová, J.; Zálešák, B.; Vostálová, J. UVA-Photoprotective Potential of Silymarin and Silybin. Arch. Dermatol. Res. 2018, 310, 413–424. [Google Scholar] [CrossRef]
  275. Katiyar, S.K.; Meleth, S.; Sharma, S.D. Silymarin, a Flavonoid from Milk Thistle (Silybum marianum L.), Inhibits UV-Induced Oxidative Stress through Targeting Infiltrating CD11b+ Cells in Mouse Skin. Photochem. Photobiol. 2008, 84, 266–271. [Google Scholar] [CrossRef] [PubMed]
  276. Svobodová, A.; Zdařilová, A.; Walterová, D.; Vostálová, J. Flavonolignans from Silybum marianum Moderate UVA-Induced Oxidative Damage to HaCaT Keratinocytes. J. Dermatol. Sci. 2007, 48, 213–224. [Google Scholar] [CrossRef]
  277. Svobodová, A.; Zdařilová, A.; Mališková, J.; Mikulková, H.; Walterová, D.; Vostalová, J. Attenuation of UVA-Induced Damage to Human Keratinocytes by Silymarin. J. Dermatol. Sci. 2007, 46, 21–30. [Google Scholar] [CrossRef]
  278. Li, L.H.; Wu, L.; Tashiro, S.; Onodera, S.; Uchiumi, F.; Ikejima, T. Activation of the SIRT1 Pathway and Modulation of the Cell Cycle Were Involved in Silymarin’s Protection against UV-Induced A375-S2 Cell Apoptosis. J. Asian Nat. Prod. Res. 2007, 9, 245–252. [Google Scholar] [CrossRef]
  279. Juráňová, J.; Aury-Landas, J.; Boumediene, K.; Baugé, C.; Biedermann, D.; Ulrichová, J.; Franková, J. Modulation of Skin Inflammatory Response by Active Components of Silymarin. Molecules 2019, 24, 123. [Google Scholar] [CrossRef] [Green Version]
  280. Li, L.H.; Wu, L.J.; Tashiro, S.I.; Onodera, S.; Uchiumi, F.; Ikejima, T. Silibinin Prevents UV-Induced HaCaT Cell Apoptosis Partly through Inhibition of Caspase-8 Pathway. Biol. Pharm. Bull. 2006, 29, 1096–1101. [Google Scholar] [CrossRef] [Green Version]
  281. Narayanapillai, S.; Agarwal, C.; Tilley, C.; Agarwal, R. Silibinin Is a Potent Sensitizer of UVA Radiation-Induced Oxidative Stress and Apoptosis in Human Keratinocyte HaCaT Cells. In Proceedings of the Photochemistry and Photobiology; John Wiley & Sons, Ltd.: Hoboken, NJ, USA, 2012; Volume 88, pp. 1135–1140. [Google Scholar]
  282. Altaei, T. The Treatment of Melasma by Silymarin Cream. BMC Dermatol. 2012, 12, 18. [Google Scholar] [CrossRef] [Green Version]
  283. Cheon, H.I.; Bae, S.; Ahn, K.J. Flavonoid Silibinin Increases Hair-Inductive Property via Akt and Wnt/β-Catenin Signaling Activation in 3-Dimensional-Spheroid Cultured Human Dermal Papilla Cells. J. Microbiol. Biotechnol. 2019, 29, 321–329. [Google Scholar] [CrossRef]
  284. Sharifi, R.; Pasalar, P.; Kamalinejad, M.; Dehpour, A.R.; Tavangar, S.M.; Paknejad, M.; Mehrabani Natanzi, M.; Nourbakhsh, M.; Ahmadi Ashtiani, H.R.; Akbari, M.; et al. The Effect of Silymarin (Silybum marianum) on Human Skin Fibroblasts in an In Vitro Wound Healing Model. Pharm. Biol. 2013, 51, 298–303. [Google Scholar] [CrossRef]
  285. Tabari, S.A.; Carpi, S.; Polini, B.; Nieri, P.; Esfahani, M.L.; Moghadamnia, A.A.; Ghorbani, H.; Ranaei, M.; Kazemi, S. Topical Application of Silymarin Enhances Cutaneous Wound Healing in Rats. South African J. Bot. 2019, 124, 494–498. [Google Scholar] [CrossRef]
  286. Oryan, A.; Tabatabaei Naeini, A.; Moshiri, A.; Mohammadalipour, A.; Tabandeh, M.R. Modulation of Cutaneous Wound Healing by Silymarin in Rats. J. Wound Care 2012, 21, 457–464. [Google Scholar] [CrossRef]
  287. Vostálová, J.; Tinková, E.; Biedermann, D.; Kosina, P.; Ulrichová, J.; Svobodová, A.R. Skin Protective Activity of Silymarin and Its Flavonolignans. Molecules 2019, 24, 1022. [Google Scholar] [CrossRef] [Green Version]
  288. Ebrahimpour Koujan, S.; Gargari, B.P.; Mobasseri, M.; Valizadeh, H.; Asghari-Jafarabadi, M. Effects of Silybum marianum (L.) Gaertn. (Silymarin) Extract Supplementation on Antioxidant Status and Hs-CRP in Patients with Type 2 Diabetes Mellitus: A Randomized, Triple-Blind, Placebo-Controlled Clinical Trial. Phytomedicine 2015, 22, 290–296. [Google Scholar] [CrossRef]
  289. Ebrahimpour-koujan, S.; Gargari, B.P.; Mobasseri, M.; Valizadeh, H.; Asghari-Jafarabadi, M. Lower Glycemic Indices and Lipid Profile among Type 2 Diabetes Mellitus Patients Who Received Novel Dose of Silybum marianum (L.) Gaertn. (Silymarin) Extract Supplement: A Triple-Blinded Randomized Controlled Clinical Trial. Phytomedicine 2018, 44, 39–44. [Google Scholar] [CrossRef]
  290. Derosa, G.; D’Angelo, A.; Maffioli, P. The Role of a Fixed Berberis Aristata/Silybum marianum Combination in the Treatment of Type 1 Diabetes Mellitus. Clin. Nutr. 2016, 35, 1091–1095. [Google Scholar] [CrossRef]
  291. Di Pierro, F.; Putignano, P.; Villanova, N.; Montesi, L.; Moscatiello, S.; Marchesini, G. Preliminary Study about the Possible Glycemic Clinical Advantage in Using a Fixed Combination of Berberis Aristata and Silybum marianum Standardized Extracts versus Only Berberis Aristata in Patients with Type 2 Diabetes. Clin. Pharmacol. Adv. Appl. 2013, 5, 167–174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  292. Hahn, H.J.; Jung, H.J.; Schrammek-Drusios, M.C.; Lee, S.N.; Kim, J.H.; Kwon, S.B.; An, I.S.; An, S.; Ahn, K.J. Instrumental Evaluation of Anti-Aging Effects of Cosmetic Formulations Containing Palmitoyl Peptides, Silybum marianum Seed Oil, Vitamin E and Other Functional Ingredients on Aged Human Skin. Exp. Ther. Med. 2016, 12, 1171–1176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  293. AlAnbari, H.; Sahib, A.; Raghif, A. Effects of Silymarin, N-Acetylcysteine and Selenium in the Treatment of Papulopustular Acne. Oxid. Antioxid. Med. Sci. 2012, 1, 201–207. [Google Scholar] [CrossRef]
  294. Curcio, A.; Romano, A.; Cuozzo, S.; Di Nicola, A.; Grassi, O.; Schiaroli, D.; Nocera, G.F.; Pironti, M. Silymarin in Combination with Vitamin C, Vitamin E, Coenzyme Q10 and Selenomethionine to Improve Liver Enzymes and Blood Lipid Profile in NAFLD Patients. Medicina 2020, 56, 544. [Google Scholar] [CrossRef] [PubMed]
  295. Hajiaghamohammadi, A.A.; Ziaee, A.; Oveisi, S.; Masroor, H. Effects of Metformin, Pioglitazone, and Silymarin Treatment on Non-Alcoholic Fatty Liver Disease: A Randomized Controlled Pilot Study. Hepat. Mon. 2012, 12, 6099. [Google Scholar] [CrossRef]
  296. Aller, R.; Izaola, O.; Gómez, S.; Tafur, C.; González, G.; Berroa, E.; Mora, N.; González, J.M.; De Luis, D.A. Effect of Silymarin plus Vitamin E in Patients with Non-Alcoholic Fatty Liver Disease. A Randomized Clinical Pilot Study. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 3118–3124. [Google Scholar]
  297. Abenavoli, L.; Greco, M.; Nazionale, I.; Peta, V.; Milic, N.; Accattato, F.; Foti, D.; Gulletta, E.; Luzza, F. Effects of Mediterranean Diet Supplemented with Silybin-Vitamin E-Phospholipid Complex in Overweight Patients with Non-Alcoholic Fatty Liver Disease. Expert Rev. Gastroenterol. Hepatol. 2015, 9, 519–527. [Google Scholar] [CrossRef]
  298. Federico, A.; Dallio, M.; Gravina, A.G.; Diano, N.; Errico, S.; Masarone, M.; Romeo, M.; Tuccillo, C.; Stiuso, P.; Morisco, F.; et al. The Bisphenol a Induced Oxidative Stress in Non-Alcoholic Fatty Liver Disease Male Patients: A Clinical Strategy to Antagonize the Progression of the Disease. Int. J. Environ. Res. Public Health 2020, 17, 3369. [Google Scholar] [CrossRef] [PubMed]
  299. Solhi, H.; Ghahremani, R.; Kazemifar, A.M.; Yazdi, Z.H. Silymarin in Treatment of Non-Alcoholic Steatohepatitis: A Randomized Clinical Trial. Casp. J. Intern. Med. 2014, 5, 9–12. [Google Scholar]
  300. Wah Kheong, C.; Nik Mustapha, N.R.; Mahadeva, S. A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis. Clin. Gastroenterol. Hepatol. 2017, 15, 1940–1949.e8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  301. Navarro, V.J.; Belle, S.H.; D’Amato, M.; Adfhal, N.; Brunt, E.M.; Fried, M.W.; Rajender Reddy, K.; Wahed, A.S.; Harrison, S. Silymarin in Non-Cirrhotics with Non-Alcoholic Steatohepatitis: A Randomized, Double-Blind, Placebo Controlled Trial. PLoS ONE 2019, 14, e0221683. [Google Scholar] [CrossRef] [Green Version]
  302. Abbasirad, F.; Shaygannejad, V.; Hosseininasab, F.; Mirmosayyeb, O.; Mahaki, B.; Moayedi, B.; Esmaeil, N. Significant Immunomodulatory and Hepatoprotective Impacts of Silymarin in MS Patients: A Double-Blind Placebo-Controlled Clinical Trial. Int. Immunopharmacol. 2021, 97, 107715. [Google Scholar] [CrossRef]
  303. Luangchosiri, C.; Thakkinstian, A.; Chitphuk, S.; Stitchantrakul, W.; Petraksa, S.; Sobhonslidsuk, A. A Double-Blinded Randomized Controlled Trial of Silymarin for the Prevention of Antituberculosis Drug-Induced Liver Injury. BMC Complement. Altern. Med. 2015, 15, 334. [Google Scholar] [CrossRef] [Green Version]
  304. Marjani, M.; Baghaei, P.; Dizaji, M.K.; Bayani, P.G.; Fahimi, F.; Tabarsi, P.; Velayati, A.A. Evaluation of Hepatoprotective Effect of Silymarin among under Treatment Tuberculosis Patients: A Randomized Clinical Trial. Iran. J. Pharm. Res. 2016, 15, 247–252. [Google Scholar] [CrossRef]
  305. Heo, E.; Kim, D.K.; Oh, S.H.; Lee, J.K.; Park, J.H.; Chung, H.S. Effect of Prophylactic Use of Silymarin on Anti-Tuberculosis Drugs Induced Hepatotoxicity. Tuberc. Respir. Dis. 2017, 80, 265–269. [Google Scholar] [CrossRef]
  306. Moayedi, B.; Gharagozloo, M.; Esmaeil, N.; Maracy, M.R.; Hoorfar, H.; Jalaeikar, M. A Randomized Double-Blind, Placebo-Controlled Study of Therapeutic Effects of Silymarin in β-Thalassemia Major Patients Receiving Desferrioxamine. Eur. J. Haematol. 2013, 90, 202–209. [Google Scholar] [CrossRef] [PubMed]
  307. Gharagozloo, M.; Karimi, M.; Amirghofran, Z. Immunomodulatory Effects of Silymarin in Patients with β-Thalassemia Major. Int. Immunopharmacol. 2013, 16, 243–247. [Google Scholar] [CrossRef] [PubMed]
  308. Hagag, A.A.; Elfrargy, M.S.; Gazar, R.A.; El-Lateef, A.E.A. Therapeutic Value of Combined Therapy with Deferasirox and Silymarin on Iron Overload in Children with Beta Thalassemia. Mediterr. J. Hematol. Infect. Dis. 2013, 5, 1–7. [Google Scholar] [CrossRef] [Green Version]
  309. Balouchi, S.; Gharagozloo, M.; Esmaeil, N.; Mirmoghtadaei, M.; Moayedi, B. Serum Levels of TGFβ, IL-10, IL-17, and IL-23 Cytokines in β-Thalassemia Major Patients: The Impact of Silymarin Therapy. Immunopharmacol. Immunotoxicol. 2014, 36, 271–274. [Google Scholar] [CrossRef]
  310. Hagag, A.; Elfaragy, M.; Elrifaey, S.; Abd El-Lateef, A. Therapeutic Value of Combined Therapy with Deferiprone and Silymarin as Iron Chelators in Egyptian Children with Beta Thalassemia Major. Infect. Disord.-Drug Targets 2015, 15, 189–195. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Chemical structures of the phytoconstituents present in silymarin.
Figure 1. Chemical structures of the phytoconstituents present in silymarin.
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Figure 2. Various molecular targets for silymarin.
Figure 2. Various molecular targets for silymarin.
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Figure 3. Various hepatoprotective modes of action of silymarin.
Figure 3. Various hepatoprotective modes of action of silymarin.
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Figure 4. Various anti-diabetic mechanisms of silymarin.
Figure 4. Various anti-diabetic mechanisms of silymarin.
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Figure 5. Anti-cancer mechanisms of silymarin.
Figure 5. Anti-cancer mechanisms of silymarin.
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Figure 6. Various mechanisms responsible for the neuroprotective effects of silymarin.
Figure 6. Various mechanisms responsible for the neuroprotective effects of silymarin.
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Figure 7. Functional triad of silymarin and its associated pharmacological properties.
Figure 7. Functional triad of silymarin and its associated pharmacological properties.
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Table 1. Experimental hepatoprotective activity of silymarin.
Table 1. Experimental hepatoprotective activity of silymarin.
Study ModelDose/Concentration UsedPossible Target Site/Mechanism of ActionReference
CCl4-induced hepatotoxicity200 mg/kg p.o
  • Decrease in the levels of ALP, SGPT, and SGOT
  • Reverses the altered expressions of α-SMA
CCl4-induced hepatotoxicity200 mg/kg p.o
  • Reduction in the levels of γ-GT, SGPT, SGOT, ALP, TGF-β1, IL-6 and hydroxyproline
  • Down-regulation of α-SMA expressions
Valproic acid-induced hepatotoxicity25 and 50 mg/kg
  • Reduction in the levels of LDH, SGPT, SGOT, ALP
  • Increase in GSH levels
Thioacetamide-induced hepatotoxicity100 mg/kg p.o
  • Down-regulation of TGF-β, AP-1, α-SMA, MMP-2 and 13, COL-α1, TIMP-1 and 2 and KLF6 expressions
Fructose-induced NAFLD400 mg/kg/day p.o.
  • Reduction in MDA, SGPT, SGOT, hepatic TG, CH and LDL
Diclofenac-induced hepatotoxicity 200 mg/kg p.o.
  • Decrease in the levels of MDA, ALP, SGPT, SGOT and TNF-α
  • Elevation in the level of SOD, GSH and CAT
CCl4-induced hepatotoxicity and HSC cells20 and 100 mg/kg p.o.
  • Down-regulation of MCP-1, TGF-β and collagen 1 expression
CCl4-induced hepatotoxicity100 mg/kg i.p.
  • Reduction in the levels of MDA, GSH, LDL, TG, SGPT, SGOT and ALP
CCl4-induced hepatotoxicity 100 mg/kg i.p. 5 times a week for 4 weeks
  • Decrease in TG, CH, VLDL-C, ALP, SGPT and SGOT levels
  • Increase in the levels of SOD, GSH and GST
  • Reduction in levels of TBARS, TGF-β1, TNF-α, IL-6, hydroxyproline and resistin
Acetaminophen-induced hepatotoxicity200 mg/kg p.o.
  • Decrease in the levels of SGPT and SGOT
  • Elevation in γ-GT and MPO levels
NASH rats200 mg/kg p.o
  • Reduction in the levels of serum insulin, HOMA-IR, SGOT, SGPT, LDL, TG and TNF-α
HFD-induced NAFLD5–10 mL/kg p.o. for 8 weeks
  • Elevation in the levels of SOD, CAT and PPARα
  • Reduction in levels of MDA, TNF-α, IL-6, SREBP-1c, FAS and LXRα
MCD diet-induced NASH105 mg/kg/day p.o. for 8 weeks
  • Up-regulation of the Nrf2 pathway
  • Decrease in the levels of TNF-α, IL-6, IL-1β, IL-12β, p-IKKα/β, p-IkBα and p-p65
  • Down-regulation of the NF-κB pathway
MCD diet-induced NASH
  • Reduction in the levels of SGPT and SGOT
  • Increase in TNF-α, TGF-β and MDA levels
  • Modulates caspase-3 activation
Restraint of stress-induced acute liver injury 100 mg/kg
  • Decrease in MDA and 4-HNE levels
  • Inhibition of JNK activation
  • Decrease in the mRNA levels of IL-1β, IL-6, TNF-α and CCL2
  • Down-regulation of Bid, Bax and caspase-3 and 8, as well as PARP cleavage
HepG2 cells and HFD-induced liver inflammation50 or 100 mg/kg per day
  • Inhibition in colocalization of NLRP and α-tubulin
  • Down-regulation of cleaved caspase-1 and thioredoxin-interacting protein
  • Prevents release of IL-1β
600 mg/kg per day p.o. for 10 days
  • Reduction in the levels of c-Kit, c-Myc, Oct3/4 and SSEA-1 markers
  • Decrease in the levels of MDA, SGPT, SGOT and MPO
HepG2 cells (Benzo[a]pyrene-induced hepatotoxicity)0–40 µM
  • Up-regulation of Nrf2 and PXR
  • Prevents DNA damage
CCl4-induced hepatoxicity 50 and 200 mg/kg
  • Reduction in TGF-β and α-SMA expression
  • Decrease in the levels of hyaluronic acid
  • Suppresses Kupffer cells activation
Zidovudine and isoniazid-induced liver toxicity100 mg/kg
  • Elevation in the levels of SOD, CAT
  • Reduction in the levels of MDA, SGPT, SGOT and ALP
Table 3. Experimental anti-cancer activity of silymarin.
Table 3. Experimental anti-cancer activity of silymarin.
Type of CancerStudy ModelDose/Concentration UsedPossible Target Site/Mechanism of ActionReference
Bladder cancerT24 and UM-UC-3 cells10 μm
  • Down-regulation of the actin cytoskeleton and PI3K/Akt pathway
Breast cancerMDA-MB-231 and MCF-7 breast cancer cells in vivo xenograft tumor model0–200 25 μg/mL
and 50 mg/kg
  • Reduction in the levels of Bcl-2, p-38 and p-ERK1/2
  • Elevation in Bax, cleaved poly-ADP ribose polymerase, cleaved caspase-9, and JNK level
MCF-7 cells10–100 μM
  • Inhibition of BCRP mRNA expression and cell viability
4T1 tumor-bearing BAlB/c mice and myeloid-derived suppressor cells 150 mg/kg
  • Reduction in TNF-α, IL1β and CCR2 levels
  • Improved T cell count
MCH-7 and MDA-MB-231 cells30–90 μM
150–250 μM
  • Reduction in MMP-2 and 9 protein expression
  • Elevation in E-cadherin expression and reduction in N-cadherin expression
  • Inhibition of NLRP3 inflammasome activation
MDA-MB-231 cells0–400 μM
  • Reduction in the expression of Cdc42 and D4-GDI mRNA
MDA-MB-231 cells50–350 μM
  • Inhibition of MMP-2 via inhibition of STAT3
MCH-7 cells
  • Reduction in AP-1 dependent MMP-9 gene expression
MCF-7 cells
  • Down-regulation of MMP-9 and VEGF expression
MDA-MB-231 and T-47D
  • Reduction in cytosolic free β-catenin level
  • Down-regulation of LPR6 and Axin2 expression
Colorectal cancerAzoxymethane-induced colon carcinogenesis model300 mg/kg p.o. for 7 days
  • Reduction in the number of preneoplastic lesions
  • Over-expression of Bax protein level
  • Down-regulation of Bcl-2 protein level and IL1β, TNF-α and MMP-7 gene expression
SW480 and SW620 cells300 μM
  • Elevation in death receptor 4/5 mRNA expression
  • Activation of caspase-9
  • Increase in expression of TRAIL
HCT116 and SW480 cells0–200 μg/mL
  • Downregulation of CD1 levels
HCT116, SW480, LoVo and HT-29 cells
  • Inhibition of p38, ERK1/2 and GSK3β protein expression
Xenograft tumor model
  • Inhibition of the PP2Ac/ AKT Ser473/mTOR pathway
  • Inhibition of cancer stem-like cell development
Gastric cancerASG human gastric cancer cells
In vivo xenograft tumor model
20–120 μg/mL
and 100 mg/kg
  • Reduction in the levels of Bcl-2 and p-ERK1/2
  • Elevation in Bax, cleaved poly-ADP ribose polymerase, cleaved caspase-9, p-P38 and JNK level
BGC-823 cells0–200 µM
  • Elevation in the levels of Bax
  • Activation of caspase-3
MGC803 cells0–200 µM
  • Increase in caspase-3 and 9 expression
  • Inhibition of p-STAT3, CDK1 and Cyclin B1 protein expression
  • Reduction in Mcl-1, Bcl-xL and survivin levels
Hepatocellular carcinomaHep G2 cells0–200 μM
  • Increase in ceramide secretion
  • Elevation in miRNA levels
HCC cells
  • Inhibition of EGFR-dependent Akt signaling
Hep G2 cells12.1–482.4 µg/mL
  • Decrease in the levels of CXC receptor-4 protein
  • Down-regulation of the Slit-2/Robo-1 pathway
Hep G2 cell model and tumor xenograft model50–200 µM
  • Elevation in the apoptotic index and caspase-3 activity
  • Down-regulation of Bcl-2, survivin and cyclin D1 level
  • Reduction in Notch1 intracellular domain (NICD), RBP-Jk and Hes1 protein expression
N-nitrosodiethyl-amine-induced liver cancer1000 ppm
  • Inhibition of the recruitment of mast cells
  • Reduction in MMP-2 and 9 expression
Laryngeal carcinomaHep 2 cells60–300 μM
  • Down-regulation of survivin expression
LeukemiaK562 cells0–100 μg/mL
  • Inhibition of telomerase activity
Lung cancerLA795, NCI-H1299 cells and
tumor xenograft models
100 mg/kg
  • Inhibition of TMEM16A
  • Reduction in vimentin, N-cadherin and β-catenin levels
  • Elevation in E-cadherin levels
  • Down-regulation of CD1 expression
Oral cancerHSC-4, YD15 and Ca9.22 cells
tumor xenograft models
40–80 μg/mL
200 mg/kg/day p.o. for 5 weeks
  • Elevation in the expression of death receptor 5 and cleaved caspase-8 levels
MC3 and HN22 cells
  • Elevation in Bim expression
  • Reduction in ERK1/2 levels
SCC-25 cells50 and 100 μM
  • Reduction in Bcl-2 gene expression
  • Over-expression of Bax, caspase-3 and caspase-9 genes
Ovarian cancerA2780s and PA-1 cells50 and 100 µg/mL
  • Amplification of p53, p21, p27 and Bax protein expression
  • Decrease in Bcl-2 and CDK2 protein expression
  • Activation of caspase-9 and 3
Prostate cancerPC-3 and DU-145 cells
  • Reduction in cytosolic free β-catenin levels
  • Down-regulation of LPR6 and Axin2 expression
DU-145 cells15.6 to 1000 μM
  • Activation of SLIT2 protein
  • Down-regulation of CXC receptor 4 expression
Skin cancerDMBA–TPA-induced skin papilloma and A431 cells12.5–50 µM
  • Reduction in MAPK/ERK1/2 levels and up-regulation of JNK1/2 and p38 expression
A375 and Hs294t cells 0–40 μg/mL
  • Reduction in β-catenin, MMP-2 and MMP-9 levels
  • Elevation in CK1α and GSK-3β levels
DMBA-TPA 2-stage skin carcinogenesis9 mg topically
  • Down regulation of NO, TNF-α, IL-6, IL -1β, COX-2, iNOS and NF-κB
A375 and Hs294t cells
tumor xenograft models
0–60 μg/mL and
500 mg/kg
  • Up-regulation of Bax protein expression
  • Reduction in VEGF, CD31, Bcl-2 and Bcl-xl protein expression
  • Reduction in MMP-2, PCNA and CDK levels
MCF-7 and NCIH-23 cell lines12.5–200 µg/mL
  • Up-regulation of caspase-3, p53 and APAF gene expression
N-Butyl-N-(4-hydroxybutyl) nitrosamine-induced carcinogenesis1000 ppm
  • Down-regulation of cyclin D1 expression causing G1 cell arrest
U266 MM cell50–200 μM
  • Reduction in p-Akt, PI3K and p-mTOR protein expression
Table 4. Cellular pathways modulated by silymarin and its flavonolignans to induce anti-cancer activity.
Table 4. Cellular pathways modulated by silymarin and its flavonolignans to induce anti-cancer activity.
Type of CancerCellular Pathway ModulatedReferences
Bladder cancer↓ PI3K-PKB/Akt signaling pathway[120]
Cervical/ovarian cancer↓ MAPK/ERK1/2 and MAPK/p38 signaling pathway
↓ Bcl-2-mediated anti-apoptosis
Prostate cancer↓ CDK, MAPK/ERK1/2, and Wnt/β-catenin signaling pathway[129,159,160]
Skin cancer↑ p53-mediated apoptosis and MAPK/p38 signaling pathway
↓ MAPK/ERK1/2, MAPK/JNK1 and Wnt/β-catenin signaling pathway
Lung cancer↑ Multiple MAPK signaling pathways
↓ CDK signaling pathway
Liver cancer (Hepatocellular carcinoma)Bcl2-mediated anti-apoptosis
p53, Bax and APAF-1-mediated apoptosis
↓ Slit-2/Robo-1 pathway and Notch pathway
Breast cancer↓ MEK/ERK and Wnt/β-catenin signaling pathway
↓ Bcl-2-mediated anti-apoptosis
Oral cancer↑ Bim-mediated apoptosis
↓ MAPK/ERK1/2 signaling pathway
Colorectal cancer↓ PP2A/AKT/mTOR, MAPK/ERK1/2 and MAPK/p38 signaling pathway
↓ Bcl-2-mediated anti-apoptosis
↑ Bax-mediated apoptosis
Gastric cancer↓ MAPK/ERK signaling pathway
↑ MAPK/p38 signaling pathway
Peripheral blood cancer↓ PI3K-PKB/Akt signaling pathway
↑ Caspase-3-mediated apoptosis
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Wadhwa, K.; Pahwa, R.; Kumar, M.; Kumar, S.; Sharma, P.C.; Singh, G.; Verma, R.; Mittal, V.; Singh, I.; Kaushik, D.; et al. Mechanistic Insights into the Pharmacological Significance of Silymarin. Molecules 2022, 27, 5327.

AMA Style

Wadhwa K, Pahwa R, Kumar M, Kumar S, Sharma PC, Singh G, Verma R, Mittal V, Singh I, Kaushik D, et al. Mechanistic Insights into the Pharmacological Significance of Silymarin. Molecules. 2022; 27(16):5327.

Chicago/Turabian Style

Wadhwa, Karan, Rakesh Pahwa, Manish Kumar, Shobhit Kumar, Prabodh Chander Sharma, Govind Singh, Ravinder Verma, Vineet Mittal, Inderbir Singh, Deepak Kaushik, and et al. 2022. "Mechanistic Insights into the Pharmacological Significance of Silymarin" Molecules 27, no. 16: 5327.

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